Recent Advances in Surgery—12 Roshan Lall Gupta
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Glimpses of Progress in SurgeryCHAPTER 1

Roshan Lall Gupta
 
TISSUE ENGINEERING
Tissue engineering may allow the patient's own cells to be obtained and seeded onto bio-degradable scaffolds that permit the formation of a particular tissue. These tissues can be employed to repair tissue defects caused by disease of trauma. Furthermore, tissue engineering may allow the ex-vivo engineering of tissue by means of three-dimensional bioscaffolds seeded with mature cell or stem cells and cultivation in bioreactors leading to the formation of whole tissues or organs, e.g. liver, heart, cartilage, etc.
MSCs are good candidates for tissue engineering protocols. Several scaffolds are currently available and may be classified as biologically derived polymers isolated from extracellular matrix, plants, seaweeds (e.g. collagen type 1 or fibronectin alginate from brown algae) or synthetic material (e.g. hydroxyapatite, tricalcium phosphate, polyactide and polyglycolide) or a combination of both.
Mesenchymal stem cells (MSCs) are characterized by their capacity for self-renewal and the production of multiple lineages whereas MSCs exist in many other tissues, e.g. skeletal muscle, fat, spinal membrane.
Embryonic stem cells offer higher pluripotency but remain problematic in clinical use because of ethical issues. In contrast MSCs harvested from adult organisms are ethically uncomplicated and readily available. However, the harvesting of these cells requires invasive procedures and adult MSCs have poor quality when compared with embryonic stem cells (Baxter et al, 2004; Roura et al, 2006).1,2
Stem cells with fetal origins have the potential to offer the ideal balance between quality and ethics. Fetal cells from fetal tissue such as umbilical cord, umbilical cord blood or placenta may lie in between (Embryonic and adult) with respect to quality and quantity.3
This is an attractive source for clinical applications and more studies should be carried out.
Polyglycolic acid nonwoven mesh tubes coated with copolymer solution were seeded with autologous bone marrow derived mononuclear cells and a living autologous vascular graft with growth potential 2developed. This is for advancing the field of congenital heart surgery. The currently available synthetic vascular grafts such as PTF lack growth potential and present problems related to biocompatibility including thrombosis, ectopic calcification and increased susceptibility to infection.
Due to lack of growth potential the surgery needs to be delayed until the patient recipient has grown to a suitable size to allow for inflammation of an adult size graft.
Tissue engineered graft in the surgical repair of congenital anomalies is cearly established.4,5
Mesenchymal stem cells are an attractive cell source for regenerative medicine.
Bone marrow aspirate is obtained from the iliac crest. Synovium is harvested from the knee joint. Adipose tissue can be harvested from perinephric fat tissue. Muscle was harvested from anterior tibial muscles.
Cells from various sources were studied. Synovium and muscle derived cells had a higher proliferation potential than bone marrow and adipose derived cells. The earlier types had much more chondrogenic potential.
Transplanting autologous chondrocytes cultured in collagen gel has been reported for the treatment of full thickness defects of cartilage.6
Neovascularization is a critical step in tissue engineering applications, since implantation of voluminous grafts without sufficient vascularity results in hypoxic cell death of central tissues. A three dimensional spheroidal coculture system consisting of human umbilical vein endothelial cells have been developed to improve angiogenesis in tissue engineering. Human umbilical vein endothelial capillary grown in collagen gels are able to form luminized capillary like structures and there is stimulatory effect of fibroblasts on endothelial cell sprouting.7
 
Bioengineered Intestinal Mucosa
Biodegradable polyester scaffolds have proved useful for growing neointestinal tissue both in vitro and in vivo. These scaffolds allow cells to attach and grown in three dimensional space while nutrient flow is maintained throughout the matrix.
The ability of neonatal derived intestinal organoids to form neomucosa has been well established (Tait et al, 1994).8 These epithelial organoids are multicullar units with a mesenchymal core surrounded by a polarized intestinal epithelium and contain all of the cells of a full thickened intestinal mucosal section. Future refinement can lead to advances in the development of a tissue engineering intestine which could lead to improved treatment of patients with loss of small intestinal function.9
 
Tissue Engineering of Vascular Conduits
To compensate for cardiomyocyte loss skeletal myoblasts have been implanted in the region of the infarct. Intracoronary infusion of myoblasts 3in patients with acute myocardial infarctions have demonstrated improved left ventricular ejection fraction and end-systolic volume.10 A phase I clinical trial by Menasche and colleagues11 included patients who had extensive infarct rendering that region nonfunctioning without any viable cardiomyocytes on PET scan.
Muscle biopsy was performed from patient's thigh and myoblasts were expanded in culture and then injected around the Infarct at the time of bypass surgery. At 1 to 2 years postoperatively an improved function demonstrated increased NYHA functional class (2.7 preoperatively to 1.6 postoperatively), Ejection Fraction (24 to 32%) and systolic thickening by Echo at the site of implant in 63 percent. The postoperative PET scan showed some viability in the infarct region that was not present preoperatively PET scan showed some viability in the infarct region that was not present preoperatively. Unfortunately, ventricular arrhythmias developed in many of these patients and they required insertion of an implantable cardioverter defibrillator. This is because myoblasts, do not express gap junction proteins and remain electrically-insulated, and they do not beat with the host myocardium.12
An alternative option has been the progenitor cells can be expanded in vitro to have a sufficient number of cells available to populate the infarct region. The engrafted cells expressed muscle proteins and participated in the angiogenesis by forming endothelial cells and smooth muscle cells. Observed sub-epicardial injection of autologous bone marrow stem cells was observed to increase ejection fraction when compared with controls (46% versus 37%).13 Mamy variations on the stem cell theme exist, including angiogenic therapy to increase vascularity at the site of infarct and growth factors to increase native stem cell homing to injury myocardium. Although use of biologic therapy is in its infancy, these early results show its potential promise. Clinical trials are now proceeding to determine the efficacy of this type of cellular transplantation. Cellular transplantation is a promising approach for myocardial regeneration therapy. Atoui et al have recently demonstrated immune tolerance of marrow stem cell (MSC) implant around the infracted area.
MSCs were obtained from humans and mice, Myocardial infarctions were created in Lewis rats by proximal left coronary ligation. The animals were randomized into 3 groups. In group I (n = 20) human MSCs were implanted around the infracted area. In group II (n = 10), isogenic rat MSCs were used instead and in group III (n = 10), culture medium was used. No immunosuppression was given at any time.
In group I and II, engrafted MSCs were detected within the rat myocardium at least 4 weeks after cell transplantation. Furthermore, some of these cells started to differentiate into a mature cardiomyocytic phenotype. This study confirms the feasibility of using marrow stem cells as “universal donor cell” fascinating economic and clinical implications, whereby xenogeneic or allogeneic MSC could be expanded, 4cryopreserved and available on the shelf, ready for implantation into patients following myocardial infarction.*
Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy, the extraxellular matrix is considerably altered. Therefore, the procedure should aim at regeneration of myocardial cells and restoring the extracellular matrix function. The feasibility and safety of intrainfarct cell therapy and along with a cell seeded collagn scaffold grafted onto infracted ventricles has been evaluated by Departments of Cardiovascular Surgery at Paris, France and Buenos Aires Argentine. This showed the feasibility and safety of intrainfarct cell therapy and along with a cell seeded collagn scaffold grafted onto infracted ventricles has been evaluated by Departments of Cardiovascular Surgery at Paris France and Buenos Aires Argentine. This showed the feasibility and safety of simultaneous intramyocardial injection of bone showed the feasibility and safety of simultaneous intramyocardial injection of bone marrow cells and fixation of a bone marrow cell seeded matrix on the epicardium of the infracted ventricles. The combined approach offers further benefits. The functional recovery is good. This is becoming a promising way for creation of a bioartificial myocardium. The reduction of the scar area assessed by radioisotope studies suggest that fibrotic tissue was replaced by living cells resulting in improved myocardium elastic properties and compliance. This explains improvement in diastolic filling time.
 
Cell Therapy for Spinal Cord Injury
Spinal cord injury has no curative therapy at present. For a future efficient treatment one has to consider and combine the following approaches: 1. Tissue or cell transplantation, 2. Providing growth stimulating factors. There is direct disruption of nerve tracts with secondary damage done to oestemia and hemorrhage. The glial scar forms at the site and is a barrier for future representations of the brain.
Therefore in the acute setting, secondary damage is linked by decompression of the spinal cord by laminectomy to limit ischemia, orthopediac fixation of the involved vertebrae and high dose of steroids.
Currently, the existence of endogenous mechanisms for neural regeneration is being accepted. In multiple animal studies the presence of neural stem cells in different areas of brain has been seen. Uchida et al have documented the existence of adult neural stem cells in the subventricular zones of the brain.
During the last decade, multiple attempts in animal models of spinal cord injury have been investigated. The approaches have focused on (i) replacement of damaged neural tissue, (ii) enhancement of endogenous neural regeneration, (iii) modulation of inflammatory response after spinal cord injury.
McDonald et al differentiated murine embryonic stem cells into neural progenitor cells and transplanted these cells into a rat model of spinal cord injury with success. Transplantation of adult nrural stem cells isolated postmortem out of human brains was associated with extensive remyelination comparable with myelintation pattern of Schwann's cells in the peripheral nervous system, when transplanted in the demyelinated rat spinal cord.
Others reported improvement after transplantation of murine neural stem cells embedded in a polymer scaffold in a hemisection model in rat. Despite all the above success with cell therapy, immunological rejection has to be noted.
To circumvent this problem of rejection MSCs residing in bone marrow have received much attention. These can be cultured easily out of bone marrow and in vitro have shown trans-differentiation into neural cells.
After transplantation into brain and spinal cord their differentiation into cells with neuronal and astrocyte characteristics was reported.
Olfactory ensheathing cells have been extracted in humans and their transplantation has improved motor and sensory recover after spinal cord injury.
These results are encouraging and the autologous nature has the relative ease of obtaining these cells and is a good therapeutic treatment for spinal injury.
 
Microsphere Encapsulation of Parathyroid Hormone for Treatment of Hypoparathyroidism
A potential delivery system for PTH microspheres were subcutaneously injected into hypoparathyroid rats and serum calcium levels were measured.
It is clear that PLGA microspheres demonstrated a rudimentary form of calcium sensitive negative feedback exhibited by the parathyroid glands.6
Maintenance of calcium homeostasis in the hypothyroid patient is a complex and challenging problem. The mechanism by which PTH would control serum calcium through an interplay of bone resorption, urinary excretion and GI absorption results in a complex temporal response of serum calcium to changes in PTH secretion. As all this unfolds our effort to construct biometric drug delivery will improve.
 
Enhancing Skin Wound Healing by Direct Delivery of Intracellular ATP
A new intracellular ATP delivery technique has been developed and tested for skin wound care. One of the major pathophysiologic events in slow or nonhealing of wounds is deficient blood supply. A new technique in which highly furogenic lipid vesicles (ATP vesicles) are used to encapsulate magnesium adenosine triphosphate (Mg-ATP). The diameter of lipid vesicles is approximately 100 to 200 nm and the phospholipids are similar to those in the cell membrane.
When these vesicles come into contact with cell membrane they fuse tougher and deliver their contents into the cytosol. This circumvents the tissue ischemic damage. The study approved by the University of Louisville Animal Care Committee used 28 nude mice.
The most sell known factor that affects wounds healing is the available blood supply which brings in oxygen, nutrients, minerals, enzymes and circulating hormones and effects wound healing. The use of small unilamellar vesicles that are highly furogenic to encapsulate ATP and use of intracellular energy delivery are the innovations that will help many patients with diabetic wounds, pressure ulcers and chronic wound. The increased wound expression indicates better healing.
REFERENCES
  1. Baxter MA, Wynn RF, Jowitt SN, et al. Study of bone marrow stromal cells. Stem Cells 2004;22:675.
  1. Roura S, Farre J, Solar Botija C, et al. Effect of aging on the pluripotential capacity of human CD 105+ mesenchymal stem cells. Eur J Heart Fail 2006;8:555.
  1. Pojda Z, Machaj FK, Oldak T, et al. Nonhaemopoietic stem cells of fetal origin. Folia Histochem Cytobiol 2005;43:209.
  1. Shin Oka T, Matsumura G, Hibino N. Midterm clinical results of tissue engineered vascular autografts seeded with autologous bone marrow cells. J Thorac Cardiovasc Surg 2005;129:1330.
  1. Brennan MP, Dardik A, Hibino N, et al. Tissue engineered vascular grafts demonstrated evidence of growth and development when implanted in a juvenile animal model. Ann Surg 2008;248:370-77.
  1. Ochi M, Uchio Y, Kawasaki K. Transplantation of cartilage like tissue made by tissue engineering in the treatment of cartilage defects of the knee. J Bone Joint Surg (Br) 2002;84:571.

  1. 7 Wenger A, Kowalewski N, Stahl A, et al. Development and characterization of a sphenoidal coculture model of endothelial cells and fibroblasts in improving angiogenesis in tissue engineering. Cell Tissues Organs 2005;181:90.
  1. Tait IS, Flint N, et al. Generatio of neomucosa in vivo by transplantation of dissociated rat postnatal small intestinal epithelium. Differentiation 1994;56:91.
  1. Chen DC, Avansino JR, Agopian VG, et al. Comparison of polyester scaffolds for bioengineered intestinal jucosa. Cells Tissues Organs 2006;184:154.
  1. Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one year results of the TOPCARE-AMI Trial. J AM Coll Cardiol 2004;44:1690.
  1. Menasch P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe post infarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078.
  1. Murray CE, Whitney ML, Reinecke H. Muscle cell grafting for treatment and prevention of heart failure. J Card Fail 2002;8:5532.
  1. Patel AN, Geffner L, Vina RF, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation, prospective randomized study. J Thorac Cardiovasc Surg 2005;130:1631.
 
THE DIABETIC FOOT
An important underlying cause leading to diabetic foot problem is neuropathy.1 Sensory neuropathy leads to a loss of protective sensation. Foot trauma is unrecognized and leads to ulceration. The ulceration is often the portal of entry for bacteria, leading to cellulites and/or abscess formation. Motor neuropathy can lead to asymmetric muscle atrophy, foot deformity (equines deformity) and altered biomechanics. This leads to areas of high pressure during standing or walking and repeated trauma that may go unrecognized because of sensory deficit. Autonomic neuropathy results in loss of sweating and dry skin that leads to cracks and fissures and a portal of entry for bacteria. Diabetes is also associated with an increased risk of peripheral arterial disease and it can be a major factor in non-healing of foot ulcerations.
Diabetic patients can have significant foot infection,2,3 with much less pain and no pronounced systemic inflammatory response. A high index of suspicion is therefore required to diagnose foot infection in patients with diabetes.
The skin of the foot is a highly specialized organ. The plantar skin consists of a complex array of fascia, fibrous septae and columnar adipose that permits protection from vertical compressive and tangential shearing forces that occur during walking. The dorsal skin is bound to the underlying extensor retinaculum. Infection tracks along fascial planes and tendon sheaths. The location of a diabetic foot wound will usually lead surgeon to the underlying cause. An ulcer at the posterior border of the heel is usually the result of chronic pressure from prolonged contact with 8bedding, friction from rubbing against rough bed sheets and lack of elevation. An ulcer about the plantar foot is almost always due to (i) excessive pressure and time between the foot and the contact surface, (ii) neuropathy and (iii) deformity of the foot (equines contracture). Understanding the underlying cause will allow an effective wound care. The single best means of reducing pressure on the sole of the foot is to employ non-weight bearing of the involved limb through use of crutches or walker. This may not always be practical but effort should be made to emphasize compliance. Use of standard off-loading shoes are also recommended.5
Pain in a neuropathic foot is usually related to an underlying infection. After a thorough surgical preparation, in the emergency room, to remove debris and allow proper evaluation, the wound is probed to determine its depth and tissues involved. Osteomyelitis should be considered if the wound is deeper than the dermis layer. Most patients with diabetes who present with a severe foot infection have chronically poor glycemic control, chronic anemia, poor nutrition and deficient clinical care. Therefore, laboratory studies and necessary management is essential before embarking on active treatment.
An important initial step in treating limb threatening diabetic foot infection is to perform a timely and adequate surgical debridement.6 This entails surgical excision of all nonviable and/or infected tissue. The plantar spaces are opened by longitudinal incisions with division of plantar fascia. When pus is present in flexor tendon sheaths, these are opened and drained. In order to appropriately evaluate the viability of the soft tissues and the underlying structures, surgical debridement should be performed without the use of a tourniquet. If there is exposed bone or suspicion of osteomyelitis, cultures are obtained of this tissue. Wound is irrigated and meticulous hemostasis achieved. Most diabetic foot infections are treated with an empirically selected antibiotic regimen until cultures and sensitivity are available. In a limb threatening infection or osteomyelitis, intravenous therapy should be initiated and followed if possible by oral agents. The use of topical antibiotics has a limited place as may produce the development of resistant strains of colonized surface bacteria.7
A patient with diabetes may not give the typical history of claudication because of associated neuropathy or lack of activity. It is therefore important to evaluate the limb for peripheral arterial disease even in the absence of symptoms. If pedal pulses are not clearly palpable, further vascular studies are indicated. An ankle-brachial index (ABI) should be obtained.
There is a close association between peripheral arterial disease and coronary disease making then both a high risk for a traditional open bypass procedure. The endovascular options include percutaneous angioplasty with or without a stent These procedures cab be performed under local anesthesia and sedation and with a high rate of limb salvage.89
The standard treatment of diabetic foot ulcer includes adequate off-loading of weight, frequent ulcer debridement, wound care, treatment of infection and revascularization of ischemic limb. This standard care in many controlled trials has resulted in healing of a number of foot ulcers. However, newer therapeutic modalities that can improve healing also need to be explored.
Despite recent advances in surgical and radiologic vascular techniques, a fair number of patients with critical limb ischemia are not eligible for a revascularization procedure. This is because of anatomic location of the lesion, the extent of the disease or extensive co-morbidity. No effective pharmacologic therapy is available and amputation is often the only option left. The cost of managing a patient after amputation has been estimated to be almost twice that of a successful limb salvage.9 Therefore, exploring new strategies for ischemic limbs is of major importance. Bone marrow derived progenitor cells have been identified as a potential new therapeutic target.10
Normal wound healing is a intricate process involving various cell types, coordinated processes, and complex signaling interactions. In a diabetic wound, many of these responses to inflammatory mediators, matrix production, angiogenesis, and wound contraction have all been poor and contribute to delayed healing of a diabetic wound.10
Cell-based therapy is an attractive approach for the treatment of wounds with multiple impairments. Mesenchymal stromal cells (MSCs) are the multipotent cells derived from stroma of bone marrow and other tissues.11 The local delivery of MSC to a diabetic wound might correct wound healing impairment both indirectly by reversing local growth-factor deficiency, and directly by improving wound contraction through interaction with the extracellular matrix. The decrease in wound size might have the potential to offset diabetes-related wound-healing impairment significantly.12
In a randomized controlled trial in 28 diabetic patients with critical limb ischemia, Huang et al13 reported improvement in limb ischemia and foot ulcers. By far the most studies of cell therapy have used intramuscular implantation method or intraarterial injection. Progenitor cell-based therapy may have great clinical potential.
One of the major event in slow healing of a diabetic wound is a deficient blood supply. The decreased blood supply and reduced oxygen delivery to the wound cells results in significantly decreased cellular energy supply which has influence on healing process. Chiang et al have developed a new intracellular adenosine triphosphate (ATP) delivery technique in mice, in which highly fusogenic lipid vesicles (ATP vesicles) are used to encapsulate magnesium-adenosine triphosphate (Mg-ATP). The diameter of lipid vesicles is about 100 to 200 nm, and the phospholipids are similar to those in the cell membrane. When these lipid vesicles come into contact with the cell membrane, they fuse together and deliver their contents into the cytosol. The direct intracellular delivery of 10ATP may thus overcome tissue ischemia. The wound healing is greatly improved. The increased wound tissue VEGF expression in mice treated with ATP vesicles indicated that with direct intracellular ATP delivery, it is possible to provide a healthier environment for accelerated healing. However, more experiments using chronic wound models are needed to evaluate the use of this technique and it is not certain if this result can be extrapolated into other chronic wounds.
REFERENCES
  1. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003;361(9368):1545.
  1. Zygonis T, Roukis TS. A systematic approach to diabetic foot infections. Adv Ther 2005;22:244.
  1. Lipsky BA. A report from the International Consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev 2004;20 (Suppl. 1): S6-S8.
  1. Kerstein MD. Heel ulerations in the diabetic patients 2002;14:212.
  1. Andersen CA, Roukis TS. The diabetic foot. Surg Clin N Am 2007;87:1149.
  1. Attinger CE, Bulan E, Blume PA. Sugical debridement: The key to successful wound healing and reconstruction. Clin Pediatr Med Surg 2000;17:599.
  1. O'Meara SM, Clullum NA, Majid M, et al. Systemic review of antimicrobial agents used for chronic wound. Br J Surg 2001;88.4
  1. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis. Report of a prospective randomized trial in a selected group of patients. J Vasc Surg 1989;9:1-9.
  1. Singh S, Evans L, Datta D, et al. The cost of managing lower limb ischemia. Eur J Vasc Endovasc Surg 1996;12:359.
  1. Sprengers RW, Lips DJ, Moll FL, et al. Progenitor cell therapy in patients with critical limb ischaemia without surgical options. Ann Surg 2008;247:411.
  1. Blakytny R, Jude E. The molecular biology of chronic wounds and delayed healing in diabetes. Diabet Med 2006;23:594.
  1. Wu M, Yang L, Liu S, et al. Human embryonic mesenchymal stem cells for skin related tissue. Br J Dermatol 2006;155:282.
  1. Huang P, Li S, Han M, et al. Autologous transplantation of granulocyte colony stimulating factor-mobilised peripheral blood mononuclear cells improve ciritial limb ischemia in diabetes. Diabetes Care 2005;28:2155.
  1. Chiang B, Essick E, Ehringer W, et al. Enhancing skin wound healing by direct delivery of intracellular adenosine triphosphate. Am J Surg 2007;193:213.
 
FISTULA-IN-ANO
 
Recent Advances in Treatment
The classical lay open technique of fistulotomy is still the gold standard of treatment in most cases. Treatment, however, becomes difficult with increasing complexity, higher internal opening with major sphincter involvement or atypical and secondary tracts. Recurrence after surgery 11may occur if the initial treatment has been inadequate or post-fistulotomy wound care was poor. Underlying disease like Crohn's colotis may also be the cause.1 Complex fistulae in patients with Crohn's proctocolitis should be treated more conservatively to avoid the risk of incontinence. Seton placement is the rule in these cases and this helps the fistula to heal and allows continued drainage without forming an abscess. The use of permanent Setons until the disease subsides in a Crohn's patient is not an uncommon practice to preserve the sphincter function and drain the tract.
Medical therapy should be offered in conjunction with surgical treatment to help in suppressing the underlying disease.2
 
Fibrin Glue
This novel approach to fistula-in-ano management describes a method that stimulates healing of fistula with preservation of the sphincter mechanism as it involves no surgical interference with the musculature of the sphinct mechanism. Hedelin et al3 first described its use for plugging fistulae in 1982. The mode of action is thought to be by stimulating the growth of fibroblasts and pluripotent endothelial cells into the fistula tract to seal it off. This is achieved by using the fibronectin and collagen present in the mixture as a matrix for the cells to integrate into. These cells then lay collagen and extracellular matric in the next stage of wound healing.4 The glue is deployed after curettage of the tract. Also before application the primary opening is inspected ensure that it is not closed and that it does not lie in the high pressuse zone of the anorectum. This results in glue being pushed out of the fistula tract.
Swinscoe et al5 reviewed the literature regarding treatment outcomes using fibrin glue. The reported healing rates were variable and ranged from 10 to 74 percent. Simple fistulae reported a higher rate of healing while the complex had lower reported success rates. Shorter fistulae tend to recur more often than longer fistulae, the reason being that short fistulae do not hold the glue as well as longer tract fistulae do.6 Continence seems to be unaffected when the patient is treated with fibrin glue. Lindsey et al in a randomized controlled trial of fibrin glue vs Conventional treatment for oral fistula reported that patients treated in fibrin glue showed no evidence of incontinence whereas 15 percent of patients managed not-traditional surgery suffered postoperative incontinence. A few studies have reported the success rate of fibrin glue to closure of Crohn's fistula. The complication of glue includes formation of abscesses and new tracts in a small rumher of cases.
 
The Anal Fistula Plug
Recently, a new technology has become available. Surgisis (Cook Surgical Inc, Bloomington In). It is an advanced biomaterial that is derived from 12swine small intestinal submucosa.7 It is a strong, pliable tissue that provides a scaffold for host cells to replace and repair damaged tissue. The idea is to bridge the defect of the fistula with a biocompatible material that would act as a scaffold for the patient's own fibroblasts to come in and promote tissue healing in the fistula tract.
The technique of plug deployment is as follows: the tract is explored, probed, and irrigated gently with hydrogen peroxide. Then the apex of the plug is tied to the probe from the internal opening and the plug is dragged through to the external opening. It is then cut to fit and secured in the internal opening, thus incorporating it with the mucosa of the anorectum to close the internal opening.
A published series comparing 2 prospective cohort groups of patients undergoing plug closure versus patients undergoing fibrin glue closure, reported an 87 percent closure rate for the plug group versus a 40 percent closure rate for the glue group. A larger series,8,9 reported better success rates of 85 and 80 percent in simple and complex fistulae.
REFERENCES
  1. Garcia-Aguilar J, Belmonte C, Wong WD, et al. Anal fistula surgery. Factors associated with recurrence and incontinence. Dis Colon Rectum 1996;39:723.
  1. Scott HJNJ. Evaluation of surgery for perianal Crohn's fistula. Dis Colon Rectum 1996;39:1039.
  1. Hedelin H, Nilson AE, Teger-Nilsson A, et al. Fibrin occlusion of fistulas postoperatively. Surg Gynecol Obstet 1982;154:366.
  1. Hammond TM, Graham M, Lunniss PJ. Fibrin glue in the management of anal fistulae. Colorectal Dis 2004;6:308.
  1. Swinscoe MT, Ventakasubramaniam AK, Jayne DG. Fibrin glue for fistula in ano, the evidence reviewed. Tech Coloproctol 2005;9:89.
  1. Venkatesh KSRP. Fibrin glue application in treatment of recurrent anorectal fistula. Dis Colon Rectum 1999;42:1136.
  1. Johnson EK, Gaw JU, Armstrong DN. Efficacy of anal fistula plug versus fibrin glue in closure of anorectal fistulas. Dis Colon Rectum 2006;49:371.
  1. Champagne BJ, O'Connor LM, Fergusom M, et al. Efficacy of anal fistula plug in closure of cryptoglandular fistula, long term follow up. Dis Colon Rectum 2006;49:1817.
  1. O'Connor L, Champagne BJm Ferguson MA, et al. Efficacy of anal fistula plug closure of Crohn's anorectal fistulas. Dis Colon Rectum 2006;49:1569.
  1. Lindsey IS, Cunningham C, Mortensen NJM, et al. A randomised controlled trial of fibrin glue vs conventional treatment for and fistula. Dis color Rectum 2002;45:1608-15.
 
TESTIS-SPARING SURGERY FOR BENIGN AND MALIGNANT TUMORS
The widespread use of high frequency scrotal ultrasound has led to a marked increase in the number of incidentally detected testicular lesions. 13Frozen section examination has achieved high accuracy in the intra-operative characterisation of testicular masses of any nature.
The old dogma that the diagnosis of any testicular mass would lead to immediate orchidectomy has been confuted by the clinical experience accumulated in the last decade. Several well-conducted retrospective outcome studies with considerable follow-up suggest that the organ sparing approach is a viable modality for testicular tumors of different histology in the pediatric and adult population.15
Preservation of testicular parenchyma may be of paramount importance from a functional standpoint and may reduce the psycho-social consequences related to radical orchidectomy.
The testis is delivered through a standard inguinal incision in preparation for orchidectomy. The spermatic cord is isolated, suspended and prophylactically clamped with a soft vascular clamp or occluded with a tourniquet. The testis is then exteriorized from the same access and placed in a separate operative field consisting of a folded towel resting on the ipsilateral upper thigh to avoid potential spillage in case a malignant tumor is encountered. The gubernaculums testis is either clamped or sectioned. When cooling of the testis is performed, the testis is immersed in ice slush solution for 10 minutes after cord clamping and kept cold throughout the procedure. The tunica vaginalis is opened and testis inspected.
Operating microscope will aid in identifying and subsequently avoiding blood vessels subjacent to the tunica albuginea. The mass is localized by intraoperative ultrasound. The lesion is removed leaving a 2-5 mm rim of normal appearing testicular parenchyma around it and sent for frozen section examination (FSE). Post-excision ultrasound will confirm complete removal of the mass. IF FSE is benign, hemostasis is achieved and tunica albuginea closed. If FSE is malignant and radial orchidectomy not performed (bilateral tumors) care is taken to obtain multiple biopsies of the remaining parenchyma to rule out concomitant foci of malignancy.
FSE has recently been demonstrated to be a highly reliable method to characterize testicular masses.43,7 Testicular ischemia during spermatic cord clamping has the potential to impair endocrine and exocrine function. Sufficient experimental and clinical evidence, however, suggests that no irreversible damage occurs provided the cord clamping does not exceed 30 minutes.1 Moreover, this time span is reasonable for the entire procedure.2,8
The results of the two largest contemprorary series of men electively operated on with testis preservation have recently been presented. After a mean follow-up of about 8 and 4 years respectively, no patient experienced local or distant recurrence.2,3
The first description of testicular sparing surgery (TSS) for malignancy was reported by Richie5 who performed a hemi-orchidectomy in a patient 14with bilateral seminoma. Although infertile, the patient remained free of disease at the 2.5 year follow-up. This approach was labelled as unorthodox by the author himself, but it stimulated research and several series of TSS have appeared in the literature.9
REFERENCES
  1. Heidenreich A, Weissbach L, Holtl W, et al. Organ sparing surgery for malignant germ cell tumour of the testis. J Urol 2001;166:2161.
  1. Giannarini G, Mogorovich A, Menhini FF, et al. Long term follow up after elective testis sparing surgery for Leydig cell tumours. A single centre experience. J Urol 2007;178:872.
  1. Carmignani I, Colombo R, Gadda F, et al. Conservative surgical therapy for Leydig cell tumor. J Urol 2007;178:507.
  1. Steiner H, Holtl L, Maneschg C, et al. Frozen section analysis-guided organ sparing approach in testicular tumours. Technique, feasibility and long-term results. Urology 2003;62:508.
  1. Richie J. Simultaneous bilateral tumours with unorthodox management. World J Surg 1984;2:74.
  1. Tokue R, Sakr W, Pontes JE, et al. Accuracy of frozen section examination of testicular tumor. Urology 1992;40:512.
  1. Elbert A, Olbert P, Hegele A, et al. Accuracy of frozen section examination of testicular tumors of uncertain origin. Eur Urol 2002;41:290.
  1. Connolly SS, D' Arcy Ft, Bredin HC, et al. Value of frozen section analysis with suspected testicular malignancy. Urology 2006;67:162.
  1. Yossepowitch O, Baniel J. Role of organ sparing surgery in germ cell tumors of the testis. Urology 2004;63:421.
 
COMPOSITE TISSUE ALLOTRANSPLANTATION
After the report of the first microvascular tissue transfer1 the free transfer of autologous tissue became the mainstay for treatment of complex soft tissue defects and with reimplantation of the hand and digits, the modern era of replantation in reconstructive surgery began in the 1960s.
Composite tissue allotransplantation (CTA) is a term that includes transplantation of multiple tissues of ectodermal and mesodermal origin.2 It involves simultaneous transplantation of tissue components involving skin, muscle, nerve bone and tendons. Transplantation of hand is one of the best examples of CTA concept and it has brought the attention of the scientific community and the public to this new field of transplantation. The growth of solid organ transplantation also parallels the emergence of newer immunosuppressive drugs.
The first hand transplant was performed in Lyon France in 1998, with eventual graft loss due to noncompliance with immunosuppression.3 The clinicopathological freatures of rejection were largely confined to skin with milder involvement of muscle and tendon and sparing of bone and joints.415
Louisville School of Medicine in United States has taken lead in hand transplant surgery in the United States. Of the approximately 30 hand transplants done worldwide, 3 have been done in Louisville. A hand transplant protocol by the University was drawn up. Patient recruitment is rigid. The transplant protocol by the University was drawn up. Patient recruitment is rigid. The pretransplant psychiatric evaluation screening tests are similar to solid organ transplantation and include routine blood work out. ABO type, panel reactive antibody, infection screen, chest X-ray, cardiac evaluation, etc.
Deceased donor has to meet the standard criteria for determination of brain death. Donation after cardiac death is not considered. All donors were from the jurisdiction of the local organ procurement organization. ABO blood group compatibility and a negative crossmatch with the recipient was necessary. Absolute contraindications included active infection (HIV, hepatitis B and C, viral encephalitis), malignancy, and intravenous drug use. A detailed evaluation of the limbs of the potential donors included range of motion in all joints and absence of arthritis.
The details of the donor procedure is described briefly:5 A circumferential incision is made around the distal arm with identification of underlying veins and cutaneous nerves. Another longitudinal incision is made along the medial side of the arm over the brachial vessels to enable cannulation for cold perfusion of the limb with the University of Wisconsin solution.
The sequency of tissue repair proceeds in the following order: bony fixation, arterial revascularization, vein repair, tendon repair and nerve repair. All patients received heparin for 48 hours postoperatively.
Immunosuppression was induced with basiliximab, tacrolims, MMF and steroids, The digits were fixed in metacarpophalangeal flexion. The wrist was in a dynamic brace. A transcutaneous electrical nerve stimulation unit to decrease pain and an electric muscle stimulator were used throughout the rehabilitation course. Skin biopsies were performed to monitor rejection.
In Malaysia, an upper extremity transplantation was performed at the level of the shoulder on a 28 day old neonate born with congenital absence of one arm. The identical twin had fatal brain anomaly and was the donor of the limb. The transplanted limb grew at the same rate as the native limb and after 7 years was functional.6 One major controversy surrounding CTA is the toxicity of immunosuppression with an increased risk of cancer, organ failure and opportunistic infections.7
Many other tissues have been successfully transplanted to restore tissue loss from trauma or tumor. Simultaneous and sequential abdominal wall transplantation coincident with intestinal transplantation has been reported from University of Miami.8 A 40-year-old man received the first successful human laryngeal transplant in 1998.9 A human leukocyte antigen matched laryngopharyngeal complex including thyroid, 16parathyroids and five rings of trachea were transplanted along with anastomosis of both superior and one of the recurrent laryngeal nerves. At a follow-up of more than 7 years, the patient had excellent function, normal swallowing and good phonation.10 Other workers have reported 13 laryngeal transplantations with 90 percent graft survival at 2 years using immunosuppression similar to renal transplantation. Patients with severe disfigurement of face not amenable to reconstruction are likely to benefit from partial face transplantation. The first facial transplant was in a 38-year-old woman, disfigured by a severe dog bite who received a central and lower facial transplant in 2005.11 A sentinel skin graft was placed in the left inframammary area to monitor rejection. Sensitivity to light touch and temperature returned by 6 months, whereas motor recovery allowing complete mouth closure was achieved at 10 months. Despite two episodes of acute rejection and renal dysfunction requiring cessation of tacrolimus, the patient is satisfied with aesthetic result and is maintained on sirolimus, MMF and prednisone.
REFERENCES
  1. Buncke HJ Jr, McLearn DH, George PT, et al. Thumb replacement. Great toe transplantation by microvascular anastomosis. Br J Plast Surg 1993;26:194.
  1. Tobin GR, Breidenbach WC 3rd, Pidwell DJ. Transplantation of the hand, face and composite structures evolution and current status. Clin Plast Surg 2007;34:271-78.
  1. Dubernard JM, Owen E, Herzherg G, et al. Human hand allograft. Report on first 6 months. Lancet 1999;353:1315-20
  1. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplanation 2003;76:688.
  1. Jones JW, Gruber SA, Barker JH, et al. Successful hand transplantation, one year follow up. Louisville Transplantation Team. N Engl J Med 2000;343:468.
  1. Pathmanathan V. Arm transplantation for congenital absence of the hand. The 7-year experience. 7th International Symposium on composite tissue alotransplantation. Innsbruck Austria Soft 7-8, 2007.
  1. Dunn DL. Problems related to immunosuppression. Infection and malignancy occurring after solid organ transplantation. Crit Care Clin 1990;6:955.
  1. Selvaggi G, Levi DM, Kato T, et al. Expanded use of transplantation techniques. Abdominal wall transplantation and intestinal autotransplantation. Transplant Proc 2004;361:1561.
  1. Birchall M. Human laryngeal allograft. Shift of emphasis in transplantation. Am J Transplant 2006;6:20.
  1. Birchall MA, Lorenz RR. Laryngeal transplantation, a review. Transplant Proc 2007;39:2076.
  1. Dubernard JM, Lengele R, Morelon E, et al. Outcomes 18 months after the first human partial face transplant. N Eng JMed 2007;357:2451.
17
 
PANCREATIC ISLET TRANSPLANTATION
The incidence of diabetes is predicted to increase significantly in the next decade. It already affects about 130 million people worldwide. Despite the efficacy of insulin therapy, the devastating secondary complications, including retinopathy, nephropathy, cardiovascular disease, and neuropathy, can shorten life expectancy by as much as one third.
The Diabetes Control and Complications Trial Research Group has shown that improved glycemia control by antidiabetic drugs is associated with a decrease in both the incidence and progression of the microvascular complications of diabetes.1
The islets of Langerhans are scattered throughout the pancreatic parenchyma and normally secrete insulin from their beta cells in response to an elevation in the plasma glucose concentration. Successful transplantation of islets isolated from pancreas can restore normal control of glucose metabolism and obviate the need for insulin in patients with type 1 diabetes. In the year 2000 Shapiro and colleagues reported 100 percent success in 7 patients with multiple infusions of pancreatic islets from different donors to achieve normal glucose levels and independence from exogenous insulin.2
Several problems, however, need to be overcome. The first is related to the difficulty in isolating sufficient number or high quality donor cells. Isolation from several donors is used in a single recipient. Warnock and Shapiro from Vancouver3 illustrate their work as follows.3
“Human pancreas were obtained (with consent) from adult heart-beating cadaver organ donors through the organ procurement program. En bloc dissection of pancreas and in situ vascular perfusion with University of Wisconsin solution was done. Immediate surface cooling of pancreas was achieved with 4°C ice slush in the lesser omental sac. Pancreas were transported to transplant laboratory (about 5 hour travel time). Pancreas at laboratory were subjected to islet isolation. These were processed with collagenase perfused via the ducts, continuous chamber digestion and continuous density gradient purification. Purified islets were subjected to in vitro culture for 12 to 36 hours before transplantation.
Islets were isfused into the liver with fluoroscopic cannulation of the main portal vein. Total islet dose was infused. Immunosuppression was by sirolimus.
Their experience suggested that if ischemia and immune reaction could be circumvented, fewer islets are required to induce and maintain normoglycemia. The main predictor of insulin independence is the number of islets transplanted. One should replace more than 10,000 islets per kilogram of body weight for satisfactory glycemic function.
The International Islet Transplant registry reports that 90 percent of clinical islet transplantation have been performed by infusion into the portal vein. Although the liver site is well characterized, many of the islets 18are lost during or shortly after transplantation.4 Most recipients achieve insulin independence but the result is not everlasting. Most ultimately resume insulin injections. Although the liver has the advantage of a double arterial and vascular supply, its parenchymal oxygen tension is well below that of pancreas.
Whether the intrahepatic site is the best site for islet infusion given the 10 percent incidence of hepatic bleeding due to procedure (reported in the literature) and the rare risk of portal vein thrombosis.5 Perhaps the alternative site would avoid these issues. Although many transplantation site have been proposed, few have found their way into the clinical setting. Shapiro and his team, however, Support that infusion of islets into the liver through the portal vein remains the method of choice.6 There is however, clinical potential for pancreas and gastrointestinal wall site and the era of scaffold and chamber device should provide opportunity for a new therapeutic advance.
There is significant motivation to search for new sources for islets. Adult and embryonic pluripotent adult and embryonic stem cells have a potential to give rise to all types in the body including islets to be used as islet replacement tissue with possibility of unlimited quantities to be generated. It is, however, controversial as to what constitutes a pancreatic stem cell in adult pancreas so that to contribute to a better long-term function.3
Patients who have gone on to end-stage diabetic nephropathy, needing a kidney transplant are the candidate for whole-organ pancreas program. Those individuals are waitlisted and enter the program for simultaneous pancreas plus kidney transplant. It has been shown that quality of life is improved and there is also some improvement in peripheral neuropathy and stabilization of retinopathy. Of concern, is the growing awareness that simultaneous pancreas, kidney transplantation may carry a considerable associated morbidity and even an excess mortality rate compared with kidney transplantation alone. Furthermore, simultaneous transplantation seems to be associated with episodes of infection, rejection and surgical complications as compared to single organ kidney transplant.7,8
REFERENCES
  1. The diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977.
  1. Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in 7 patients with type 1 diabetes mellitus using a glucocorticoid free immunosuppressive regimen. N Engl J Med 2000;343:230.
  1. Warnok GL, Meloche RM, Shapiro RJ, et al. Impproved human pancreatic islet isolation for a prospective cochort study of islet trasplantation versus best medical therapy in type 1 diabetes melitus. Arch Surg 2005;140:735.

  1. 19 Bennet W, Groct CG, Larsson R et al. Isolated human islets trigter an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci 2000;105:125.
  1. Carlsson PO, Palm F, Anderssson A, et al. Chronically decreased oxygen tension in rat pancreatic islets under the kidney capsule. Transplantation 2000;69:761.
  1. Merani S, Toso C, Shapiro AMJ, et al. Optional implantation site for islet transplantation. Brit J Surg 2008;95:1449.
  1. Manske CL, Wang Y, Thomas W. Mortality of cadaveric kidney transplantation versus combined kidney pancreas transplantation in diabetic patients. Lancet 1995;346:1658.
  1. Ryan EA. Pancreas transplants for whom? Lancet 1998;351:1072.
 
NOTES (NATURAL ORIFICE TRANSLUMINAL ENDOSCOPIC SURGERY)
Notes imphis surgery performed endoscopically by initially passing a flexible endoscope transorally or transanally and then transluminally into areas, that would not otherwise be accessible endoscopically, such as the abdomen and pelvis. This entails intentional creation of openings in the wall of the stomach, color or other viscera which have so far been considered taboo and even at times worthy of ridicule.
In 2004, Kalloo et al from Johns Hopkins1 demonstrated the feasibility and safety of an oral transgastric endoscopic approach to the peritoneal cavity in a porcine model. The experience of Kalloo et al was soon followed by other transgastric peritoneal procedures in the porcine model, including tubal ligation, cholecystectomy, gastrojejunostomy, splenectomy and oophorectomy.2,3 Other procedures using natural orifice access to the peritoneal cavity (e.g. transcolonic, transvesical) have also been described.4,5
In most of the world, Notes has so for generally remained confined to the animal laboratory. The first clinical report, however was by Rao and Reddy in India, in a patient whose severe burn injury of the abdominal wall prohibited safe conventional surgery for acute appendicitis.68 Using a transoral transgastric approach they carried out a successful appendicectomy. This group has performed further successful surgery through this approach but these have been cited as personal communication and no published data is available.9
Marescaux et al at the University Hospital Strashourg France were the first to report the use of NOTES to treat cholecystectomy in a human being via transvaginal access10 and this was just a few days after the first laparoscopically assisted transvaginal cholecystectomy performed by the group at New York Columbia University Medical Center.11 Transvaginal access is well established and accepted. It has been used for years by gynecologists for diagnostic and therapeutic purposes but it has its limitations.20
Although transgastric access to the abdominal cavity seems to be the route that will dominate NOTES in the future, there are still some challenging issues, such as risk of infection or leakage and the method of gastric closure that will need to be addressed before this technique is introduced into clinical practice.
It is exciting to imagine the potential for NOTES in improving patient care but the benefits of such developments must be supported by well-audited studies. The ASGE and SAGES have constituted the National Orifice Surgery Consortium for Assessment and Research (NOSCAR) whose goal is to conduct research into this emerging field and to guide the responsible development of NOTES.12
Only time will tell whether NOTES will revolutionize abdominal surgery or it will be of transient interest. It will probably be complementary to laparoscopic surgery and become a preferred approach in a select group of patients, morbidly obese or with dense intraabdominal adhesions. The reliable closure of luminal perforation, however, remains an important issue.
REFERENCES
  1. Kalloo AN, Singh VK, Jagannath SB, et al. Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic intervention in the peritoneal cavity Gastrointest Erdosc. 2004;60:114-17.
  1. Park PO, Bergstrom M, Ikada, K, et al. Experimental studies of transgastric gall bladder surgery. Gastrointest. Endosc 2005;61:601-06.
  1. Jagannath SB, Kantsevoy SV, Vaughn CA, et al. Peroral transgastric endoscopic ligation of fallopian tubes with long-term survival in a porcine model. Gastrointest Endosc 2005;61:449-53.
  1. Fong DG, Pal RD, Thompson CC. Transcolonic endoscopic abdominal exploration a NOTES survival study in a porcine model 2007;65:312-18.
  1. Lina E, Rolanda C, Pego JM, et al. Transvaginal endoscopic peritoneoscopy: A novel 5 mm pose for intraabdominal scarles, surgery J Urol 2006;176:802.
  1. Reddy N, Rao P. Peroral transgastric endoscopic appendectomy paper presented at 45th Annual conference of the society of gastrointestinal Endoscopy of India. Feb 28-29, 2004, Jaipur India.
  1. Baron TH. Natural orifice tranluminal endoscopic surgery. Personal communication (N. Reddy). Br J Surg 2007;94:1-2.
  1. Rao GV. Transgastric appendectomy results and follow up (SAGES transgastric surgery panel) presented at SAGES Meeting Dallas, TX: 2006.
  1. Flora ED, Wilson TG, Martin I J et al. A Review of Natural Orifice Transluminal Endoscopic (NOTES) for intaabdominal surgery. Annats of Surgery 2004;247:583.
  1. Marescam X J, Dallemagne B, Perretta S et al. Surgery without scars. Report of transluminal cholecystectomy in a human being. Arch Surg 2007;142:823-27.
  1. Grady D. Doctors try new surgery for gallbladder removal. New York Times April 20, 2007.
  1. Rattner D, Kalloo A. ASGE/SAGES Working group or natural orifice transluminal endoscopic surgery. Surg Endosc 2006;20:329-33.