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Demands from health insurance organizations and hospitals to remain competitive in the health care market, as well as the impact of cost, patient satisfaction, and a quicker return to normal daily function, have pressured physicians and biotechnology manufacturers to address the needs of an evolving work-oriented society. Stemming from the initial experiences of successful early ambulation following surgery and the advantages of outpatient surgery to the patient, hospital, and physician, a trend toward more minimally invasive procedures ensued.1 Thus, to reduce operative time and complications, minimize intraoperative tissue trauma, diminish the length of hospital stays, lessen postoperative use of narcotics, and enhance postoperative outcomes, minimally invasive techniques have been developed to address morbidities associated with more open surgical procedures of the spine.

The earliest indication of spine pathology was found in Egyptian mummies dated 2900 BC and further elucidated in the Edwin Smith papyrus written circa 1550 BC. In fact, the first description of the spinal column was offered by the Egyptians in the djet symbol used for the god Osiris to represent stability, duration, and durability.² Emerging from the age of antiquity, Hippocrates has been credited as the father of spine surgery, as evidenced by his seminal teachings and writings, underlined by his principles of sound reasoning and accurate observation³; however, the first concrete delineation of operative treatment of the spinal column was proposed by Paulus of Aegina in the seventh century.⁴ He advocated and conducted direct removal of osseous tissue at the site of pathology. Since then, various approaches and techniques for operative treatment of the spine have been developed and evolved to address numerous conditions. In this chapter, we will review the evolution of minimally invasive techniques in the spine.

Cervical Spine

Endoscopic-Assisted Transoral Surgery

Fang and Ong⁵ published the first series of patients to undergo transoral decompression for irreducible atlantoaxial abnormalities in 1962; however, undue morbidity and mortality caused poor acceptance of this approach. Advancements in imaging techniques and the availability of the operative microscope improved the safety and efficacy of the approach. This approach, though, requires such wide exposures as soft/hard palate splitting and extended maxillotomities for decompressing clival abnormalities, resulting in increased operating time, complexity, prolonged recovery, and patient morbidity.⁶ Frempong-Boadu et al⁶ demonstrated the efficacy of endoscopic-assisted transoral surgery in limiting these extended approaches in a series of seven patients. One of the disadvantages of using the microscope is that the optics are located at a distance from the location of the abnormality. With the endoscope, the optics and illumination are in the field of the abnormality. With the use of the 30-degree angled endoscope, one can clearly visualize the clivus abnormality, obviating the need for extensive palatal splitting.⁶

Scoville and Whitcomb7 introduced the concept of posterior cervical disk surgery. Although the anterior approach to the cervical spine has become more popular, the posterior approach is an effective procedure in selected cases. It is indicated in cases with laterally herniated disk fragments, isolated foraminal narrowing, multilevel foraminal narrowing without central stenosis, continued root symptoms after anterior cervical diskectomy and fusion, and patients for whom anterior approaches are contraindicated; however, it is usually necessary to use moderate-size incisions and to perform significant paraspinous muscle dissection in these operations. Postoperative wound pain and muscle spasms can therefore be significant, and postoperative recovery is often relatively slow.

The microendoscopic diskectomy (MED) system was developed to minimize the tissue trauma and postoperative discomfort seen with open procedures (Fig. 1–1). It enables posterior cervical and lumbar diskectomy through a tubular retractor, with endoscopic observation. A guidewire is inserted through the posterior cervical musculature, with the tip being fluoroscopically directed to the operative disk space. Dilators are sequentially inserted through the posterior neck musculature, at the junction of the lamina and the lateral mass (Fig. 1–2). A 16 mm tubular retractor is then inserted over the largest dilator and fixed to the flexible arm assembly on the table. The endoscope is fixed inside the tubular retractor. The tubular retractor tip is positioned to expose the lateral portion of the superior and inferior laminae and the medial portion of the corresponding facet joint. After exposure has been achieved, a small curved curette is used to define the edge of the superior lamina and the lateral mass. Bone removal begins on the inferolateral portion of the superior lamina and proceeds to the superolateral portion of the inferior lamina. After palpation of the medial edge of the superior and inferior pedicles with a microprobe, bone removal is extended into the medial facet joint to expose the nerve root. Bone removal is performed with a small Kerrison punch or a high-speed drill as in open procedures. The MED system provides equally good exposure of the involved segment and decompression compared with open microdiskectomy.

FIGURE 1–2 Intraoperative lateral fluoroscopic scan confirming the position of the working channel of the microendoscopic diskectomy system for a C4–C5 foraminotomy and diskectomy.

In cadaveric studies, Roh et al8 performed posterior cervical foraminotomies using either the MED system or conventional open techniques. Their results demonstrated that the average vertical diameter of decompression and percentage of facet removed were greater for the MED technique. The transverse diameter of the laminotomy area and the average length of decompressed root were not significantly different. Transmuscular dilation with an endoscopic tubular working channel can minimize postsurgical pain and provide rapid postoperative recovery.

Thoracic Spine

Thoracoscopic Spine Surgery

Jacobaeus, a professor of internal medicine in Stockholm, Sweden, is credited with performing the first thoracoscopic procedure in 1910.⁹ As an internist, he was involved in the diagnosis and treatment of pulmonary tuberculosis, and he thought that the ability to observe the pleural space was crucial. After his initial diagnostic procedures, Jacobaeus described the technique of lysis of tuberculous pleural adhesions, which was performed with a cystoscope and a heated platinum loop.¹⁰ In 1990, with the introduction of video imaging to standard endoscopy, the modern era of thoracoscopy began. Mack et al¹¹ in the United States and Rosenthal et al¹² in Europe first reported the technique of video-assisted thoracic surgery (VATS) in 1993. Thoracoscopic spine procedures were initially implemented to treat disk herniations, pathologies of the vertebral body, and drainage of abscesses, as well as for tumor biopsies. In the ensuing years it was used in cases of scoliosis, anterior interbody fusions, osteotomies and bone grafting, corpectomies, and vertebral instrumentation for tumors and fractures.

Thoracoscopic access is achieved by temporarily deflating the lung on the ipsilateral side of the spinal exposure using a double-lumen endotracheal tube. Narrow portals are introduced through small incisions in the intercostal spaces. The endoscope is then introduced through one of the portals, with the other portals serving as working channels and being used interchangeably.

Thoracoscopy can be used to access the entire thoracic spine and thoracolumbar junction (to L2), providing visualization of the disks, vertebral bodies, and ipsilateral pedicle (Fig. 1–3). It offers several advantages over conventional open thoracotomy to treat spinal disorders. VATS allows visualization of the procedure to the entire operating team, and two surgeons may work side by side. VATS uses small incisions and a minimal amount of rib resection, and there is no spreading of the ribs, thus minimizing postoperative discomfort, reducing incisional pain, creating fewer respiratory and shoulder girdle problems, and decreasing blood loss. It has also shortened hospitalization time and length of rehabilitation after surgery.

Like most endoscopic techniques, the successful application of VATS has a steep learning curve that requires the operator to acquire the technical skills needed to use the long working arms of the endoscopic equipment. Bony dissection requires stable and precise manipulation of standard open equipment with modified longer working arms. Thus, it is crucial to use both hands to stabilize and achieve precise control over the drill, curettes, or bone rongeurs used to avoid devastating neural or vascular injuries.

Thoracoscopic sympathectomy has also been used with success for treatment of anhydrosis in an ambulatory setting. Furthermore, thoracoscopic sympathectomies have been performed with multiportal and biportal systems; even uniportal approaches are now being used.

FIGURE 1–3 Thoracoscopic surgery. The image illustrates thoracoscopic techniques to obtain thoracolumbar decompression and stabilization for a severe TIZ burst fracture.

In a further attempt to reduce tissue trauma and enhance postoperative outcome, a thoracic microendoscopic diskectomy instrumentation and approach have been developed and employed with preliminary success to treat thoracic disk herniations from a direct posterior or posterolateral endoscopic approach. Jho13 described the technique of endoscopic transpedicular thoracic diskectomy with a 0- and 70-degree 4 mm endoscope requiring relatively small 1.5 to 2 mm incisions and minimal tissue dissection. This approach avoids the need for separate skin incisions in the chest wall (required for thoracoscopic approaches) and the need for postoperative chest drainage. Chiu and Clifford¹⁴ demonstrated the safety and efficacy of posterolateral endoscopic thoracic diskectomy followed by low-energy nonablative laser for shrinkage and tightening of the disk (laser thermodiskoplasty) using a 4 mm 0-degree endoscope.

Lumbar Spine

Chemonucleolysis

In 1941, Eugene Jansen and Arnold Balls¹⁵ first isolated chymopapain, a proteolytic enzyme extracted from papaya latex. In 1956, Lewis Thomas¹⁶ administered intravenous injections of crude papain to rabbits and noticed that their ears drooped. Intrigued by Thomas’s article, Lyman Smith postulated the therapeutic use of papain to treat chondroblastic tumors. In 1963, Smith et al¹⁷ were the first to inject chymopapain into a herniated nucleus pulposus for the treatment of sciatica. This process, aptly called chemonucleolysis, alters the characteristics of the nucleus pulposus by liberation of chondroitin sulfate and keratin sulfate by hydrolysis of noncollagenous proteins of mucopolysaccharide involvement and leading to polymerization of the nucleus pulposus. It has been used safely to treat disk disease in the spine for the past three decades. Despite the extensive use of chymopapain, chemonucleolysis still provokes controversy. After more than 30 years of clinical experience, research, double-blind trials, and Food and Drug Administration (FDA) approval, differing views persist. Nordby and Javid¹⁸ published the results of a 14-year study of 3000 patients, with an 82% success rate for the first 1000 patients and an overall success rate of 87.2%; however, others have questioned the safety and indications for the use of chymopapain to treat disk disease.

Some 75 investigators in the United States and Canada administered injections to nearly 17,000 patients in phase III chemonucleolysis trials, which ended in July 1975. The results of the phase III trials were mixed, with several enthusiastic reports and several others that questioned the safety and efficacy of chymopapain.^19,20 To date there is no consensus in the neurosurgical and orthopedic communities regarding the use of chymopapain. Proper patient selection is crucial for any intervention, and this is especially true for percutaneous chemonucleolysis. Chemonucleolysis should be reserved for patients presenting with radicular symptoms, with radiological studies [magnetic resonance imaging (MRI), computed tomographic (CT), and/or myelographic scans] confirming a herniated soft disk, and who have experienced failure of conservative nonsurgical treatment. The size and shape of the disk are not factors for safe chemonucleolysis. The proponents of chymopapain claim that lack of familiarity, training, and indications could explain some of the complications. Age can be a factor because patients over 60 years of age may lack sufficient mucoprotein for hydrolysis of the herniated disk. For patients younger than 20 years of age, 80 to 90% success rates have been reported.²¹

FIGURE 1–4 Diagram showing anatomic features of the relevant structures close to the path of the needle.

Chemonucleolysis is performed with the patient placed in either a lateral or a prone position; the needle is positioned in the center of the offending disk, with fluoroscopic guidance (Fig. 1–4). The currently recommended dose is 1000 to 2000 units/disk space. With chymopapain sensitivity testing and administration of antihistamine agents before chymopapain injection, anaphylaxis has been reduced to 0.25% of total allergic reactions. The vast majority (87%) of the reported complications occurred before 1984, and no major anaphylactic complications have been reported in the United States since July 1987.²²

There is significant cost effectiveness in the use of chemonucleolysis for the treatment of intervertebral disk disease. As noted by Ramirez and David,²³ the cost of chemonucleolysis is, on average, 23% lower than that of surgical treatment of disk herniation.

Percutaneous Diskectomy

In 1975, Hijikata et al²⁴ demonstrated a percutaneous nucleotomy by utilizing arthroscopic techniques for disk removal via intradiscal access for the treatment of posterior or posterolateral lumbar disk herniations under local anesthesia. After diskography using Evans blue dye, specially designed instruments were placed in a 5 mm cannula and inserted against the lateral anulus. A circular incision was made in the anulus, and the blue-stained nucleus pulposus was removed with pituitary forceps. In 1983, Kambin and Gellman25 performed a diskectomy by inserting a Craig cannula and a small forceps into the disk space after an open laminectomy to evacuate the nucleus pulposus. In 1985, Onik et al²⁶ reported the development of a 2 mm blunt-tipped suction cutting probe for automated percutaneous diskectomy at L4–L5 or higher levels.

The selection criteria for patients undergoing percutaneous diskectomy are similar to those for patients undergoing chymopapain treatment. Patients are selected on the basis of clinical symptoms and radiological evidence that removal of the nucleus pulposus would decompress the affected nerve root. It is also important to identify the presence or absence of extruded fragments. On T2-weighted MRI scans, extruded disks appear brighter than contained disks, which exhibit dark coloration similar to that of degenerated disks. CT diskograms can demonstrate the presence or absence of extruded disk fragments. The size of the protrusion is an important factor in obtaining successful outcomes with percutaneous diskectomy. If the disk herniation is >50% of the anteroposterior diameter of the thecal sac, then there is a >90% chance that the patient will experience a poor outcome after percutaneous diskectomy. Patients with narrowed disk spaces are also poor candidates for percutaneous diskectomy.

Kambin and Sampson²⁷ initiated the use of fluoroscopy before the procedure for confirmation of the appropriate disk level. The anteroposterior view is used to confirm that the patient is in line without rotation. The lateral view should indicate that the end plates are parallel. Preoperative CT or MRI scans of the entire abdomen through the involved disk space should be obtained to avoid damaging crucial structures in a far lateral approach.

Suction diskectomy is performed with the patient in either a prone or a lateral position. Flexion of the hips reduces lumbar lordosis and allows for a larger entry zone posteriorly. The procedure is performed using mild sedation and local anesthesia. An 18-gauge, 25 cm, hubless, stainless steel trocar is inserted and advanced obliquely, with fluoroscopic guidance, toward the posterior margin of the intervertebral disk to reach the appropriate level. The starting point on the skin is usually 10 cm from the midline. When the trocar is in the appropriate position, a 2.8 mm cannula with an internal, blunt-end, tapered dilator is placed over the hubless trocar. When the cannula and dilator are in the correct position, the dilator is removed. The cannula is pressed against the anulus, and a 2 mm, open-ended, circular cutting tool is inserted through the cannula to cut a hole in the anulus. The nucleotome is advanced into the disk space. The nucleotome is 20 cm in length, with a rounded tip. The reciprocating action of the cutting tool and aspiration occur simultaneously. Saline solution is delivered to the disk space by flowing between the inner and outer cannulas, producing a suspension of macerated disk material as the inner cannula reciprocates at 180 cycles/min, permitting rapid cutting. The slurry of saline solution and disk material is aspirated through the inner cannula into a collection bottle. After the disk space has been accessed, the diskectomy can be completed in 15 to 20 min.

FIGURE 1–5 Result of using an automated percutaneous lumbar diskectomy system for a single-level disk herniation.

Minimally invasive lumbar surgery can be performed successfully using percutaneous techniques. The outcomes of more than 4500 automated or manual percutaneous lumbar diskectomies (PLDs) have been reported. The reported outcomes indicate an overall success rate of 75%, with a complication rate of 1%. Automated PLD is appropriate for patients with single-level disk disease (Fig. 1–5). It is not considered an option for patients with a history of previous chymopapain or surgical treatment for disk disease, progressive neurologic deficits, bowel or bladder problems, sequestered disk fragments, or evidence of vertebral disease (e.g., spinal stenosis or spondylolisthesis).

The role of PLD remains investigational until prospective, randomized, controlled studies reliably validate outcomes. In the future, spinal endoscopy may facilitate observation of the area of nucleotomy and increase the amount of disk removal.

Percutaneous Laser Diskectomy

Ascher and Heppner²⁸ were the first to use the technique of percutaneous laser diskectomy to treat lumbar disk disease. Their technique involved measuring the intradiscal pressure before and after laser diskectomy, using a saline manometer. They postulated that the removal of even a small volume of tissue from the disk caused a corresponding decrease in intradiscal pressure.28 This procedure is not indicated for patients with uncontained disk extrusions or disk fragments outside the disk space. The combined results of Ascher,²⁹ Choy et al,³⁰ and others demonstrated 70 to 80% rates of longlasting pain relief for more than 1000 patients. In 1990, Yonezawa et al³¹ used a neodymium:yttrium-aluminumgarnet (Nd:YAG) laser through a double-lumen needle with a fiberoptic, quartz-fiber tip to measure pressure before and after the procedure.

Percutaneous laser diskectomy is an outpatient procedure that requires percutaneous placement of a single needle in the disk space. With fluoroscopic verification of the level and placement of the needle and with coupling via a fiber, laser energy is passed into the disk space. The laser energy is transmitted in short bursts to avoid excessive heating of the adjacent tissue. The consensus is that percutaneous laser diskectomy should demonstrate indications and successes similar to those of other percutaneous modalities.

In 1992, Davis³² used a potassium-titanal-phosphate (KTP) laser for lumbar disk ablation, achieving a success rate of 80%. Producing a light that is lime green at 531 nm, the KTP laser can be coupled to a fiberoptic cable and can be easily directed into the intervertebral disk space through a spinal needle. The procedure is appropriate for patients with contained disk herniations associated with radicular symptoms. The KTP laser has also been approved for percutaneous laser diskectomy. Advances have allowed the development of side-firing probes, which provide better directional control and allow better observation. The side-firing laser probe reduces the risk of injury to such anterior structures as the vena cava, aorta, and iliac vessels. Yeung³³ recommended injecting the disks with indocyanine green (to act as a chromophore), thus maximizing delivery and minimizing the chance of injury to adjacent structures.

The holmium:YAG laser has a 2.1 μm wavelength (in the midinfrared region), which can easily be delivered to the intervertebral disk space. In contrast to the continuous-wave lasers of other systems, the holmium: YAG system has a unique pulsed laser, which enables adjustment of the pulse width and frequency, to reduce damage to adjacent tissue. In bench testing with a pulse width of 250 msec at 10 Hz and 1.6 J/pulse, no temperature increase was noted in adjacent tissues. The disk cavitation caused by the laser results in a reduction in intradiscal pressure, decreasing the force driving the herniated fragments posteriorly. The only reported complication was a case of diskitis in a series of 333 procedures described by Choy et al.³⁴ The possible complications theoretically include perforation of the aorta, vena cava, iliac vessels, or abdominal contents and cauda equina syndrome.

The results of percutaneous laser disk decompression in cases involving back and leg pain with disk protrusions are still unclear. No controlled prospective studies have been performed to evaluate the results of percutaneous laser diskectomy. The largest experience in the literature was reported by Choy et al.³⁴ They found excellent results in 87.4% in a study of 333 patients, with a mean follow-up of 26 months. Early experience with the KTP/532 device was reported by Davis,³⁵ who achieved an 85% success rate. Yeung³³ reported good to excellent results in 84% with the KTP/532 device.

Percutaneous laser diskectomy is one step in the development of safer techniques for disk removal. Various laser wavelengths have been used for this purpose, but no consensus exists regarding success with this form of treatment. Published results demonstrated 70 to 80% success rates for selected groups; unfortunately, laser diskectomy as a stand-alone procedure adds controversy to the field of percutaneous treatment of lumbar disk disease. Current techniques, however, involve manual removal of disk material with laser modulation under endoscopic control. The use of lasers under direct observation can be performed safely and effectively.

Arthoscopic Microdiskectomy

Ottolenghi and Argentina³⁶ in 1955 and Craig³⁷ in 1956 described posterolateral biopsy of the spine. In 1983 and 1986, Kambin^25,27 and co-workers combined open laminectomy with nucleotomy, via Craig instrumentation, to observe the effects of nucleus pulposus removal on the surrounding anatomic features. In 1975, Hijikata et al²⁴ developed mechanical tools for nucleotomy using similar principles. Refinements to the technique involved the use of an automated system.

Subsequent developments led to the design of a 2.7 mm glass arthroscope combined with a videodiscoscope with a single working portal.³⁸ This development enabled observation of periannular structures, including the foramina and the spinal nerve. Arthroscopic disk surgery allows removal of herniated disks via a posterolateral approach. This is accomplished with biportal access via triangulation into the intervertebral disk, with adequate irrigation and suction.³⁸

The mechanism of pain relief after arthroscopic microdiskectomy and central nucleotomy is believed to involve reduced intradiscal pressure, removal of inflammatory agents, reductions in intervertebral disk height, and lower tension on the nerve. The dramatic cessation of radicular pain after extraction of a herniated nuclear fragment in the course of an open surgical procedure proves that removing tension and irritation from the nerve root helps provide pain relief.

Small rigid arthroscopes allow inspection of the anulus, spinal nerve, and foramina. Intradiscal arthroscopic observation is not required for simple nucleotomy or disk debulking. Localization and removal of posteriorly herniated disk fragments require good arthroscopic illumination and observation. There are currently 0-, 30-, and 70-degree angled arthroscopes and flexible arthroscopes are available.

The triangular working zone has been defined as a safe zone in the posterolateral anulus, allowing safe passage of instruments with minimal risk to the exiting nerve.25,27 As the nerve exits the foramen, it extends laterally and distally, forming the anterior borders of the triangular working zone. The inferior border of this safe zone is the vertebral end plate of the lower body. It is bordered posteriorly by the articular process and superior articulating facet of the lower vertebrae and medially by the traversing root and dura (Fig. 1–6).

FIGURE 1–6 Red shaded area represents the triangular working zone (Kambin’s triangle) defined as the “safe zone” at the posterolateral anulus, allowing safe passage of endoscopic instruments to the disk space with minimal risk to the exiting nerve roots.

Uniportal access is achieved with a 5 mm internal diameter cannula, which provides access for central and posterior extraction of herniated intra-annular fragments. The instruments required for arthroscopic microdiskectomy include 18-gauge needles, guidewires, a cannulated obturator, a 6.4 mm (outer diameter) access cannula, a suction irrigation valve and cannula stopper, trephines, flexible-tip forceps, a videodiscoscope, suction forceps, and a variety of powered resecting instruments (Fig. 1–7). With uniportal access, resecting instruments and the videoscope are inserted alternately for observation and safe resection. On the other hand, an access cannula with an outer diameter of 12 to 14 mm can be used, permitting exploration of the exiting nerve and foraminal decompression. The lateral recess can be accessed through this cannula, with partial resection of the pars and facet joints. The cannula is also used to perform a mini-laminotomy and extraction of the free fragments. This device has a side fenestration that permits introduction of the videoscope; simultaneous observation and resection can thus be performed.

FIGURE 1–7 The YESS (Yeung Endoscopic Spine Surgery) system used for posterolateral diskectomy consists of multichannel endoscopes working cannulas and specialized instruments.

Numerous studies on the efficacy of arthroscopic disk surgery have been published. Kambin and colleagues25,27 reported an 87% successful outcome rate with arthroscopic microdiskectomy, and others have reported similar success. In a prospective randomized study evaluating the efficacy of microscopic disk surgery compared with endoscopic disk extraction, Mayer and Brock³⁹ achieved favorable outcomes, with minimal complications, with the percutaneous arthroscopic technique. The reported complications include diskitis, instrument breakage, and psoas hematomas; no neurovascular complications arising from posterolateral access to the intervertebral disks of the lumbar spine have been encountered. Proper patient selection makes this an attractive option, with same-day surgery, negligible blood loss, avoidance of general anesthesia, and minimization of scar tissue all contributing to satisfactory outcomes.

Percutaneous Intradiscal Radio-Frequency Thermocoagulation

Percutaneous intradiscal nucleotomy using lasers was first performed by Ascher and co-workers in 1987.^28,29 The laser energy causes vaporization of the nucleus pulposus, thus reducing the intradiscal pressure and symptoms related to the herniated disk. Radio-frequency lesioning has gained wider acceptance and is used to treat trigeminal neuralgia and create pallidotomy and thalamotomy lesions. The size of the lesion can be well controlled, and the lesion is usually placed around the tip of the electrode. A high-frequency alternating current flows from the tip of the electrode into the tissue. Most radio-frequency lesions are produced at probe temperatures of 60 to 80°C (Fig. 1–8).

Intradiscal electrothermal coagulation is a therapeutic innovation specifically designed to treat internal disk disruption. This is a condition in which the disk is rendered painful because of the development of radial fissures extending into the outer one third of the anulus fibrosus. The diagnosis of this condition is based on history and radiological findings, in the form of diskograms and/or postdiskography CT scans. Intradiscal electrothermal coagulation involves percutaneously threading a flexible heating electrode into the disk so that the electrode passes circumferentially around the inner surface of the disk. The heating of the electrode denatures the collagen of the anulus and coagulates the pain fibers supplying the anulus. Direct application of thermal energy to the intervertebral disk produces pain relief via two different mechanisms, thermal coagulation of nociceptors and increased disk stability due to contraction of collagen type I fibers.

FIGURE 1–8 Drawing demonstrating intradiscal electrothermal coagulation, performed by percutaneously threading a flexible heating electrode into the disk.

A common method of achieving temperatures of 60 to 80°C involves using a needle powered by a radiofrequency generator in the center of the nucleus. Saal and Saal40 developed a novel resistive heating catheter that can be introduced into the anulus and navigated through the nucleus and around the inner wall of the anulus. Oratec Interventions Inc. (Menlo Park, CA) has conducted several clinical trials of intradiscal electrothermal treatment for internal disk disruption. Their study included 140 patients who presented with chronic lower back pain between February 1998 and October 1998. To be eligible for that study, patients were required to satisfy the International Association for the Study of Pain criteria for internal disk disruption: reproducibility of pain with stimulation of the affected disk and CT evidence of a grade III annular tear. Fifty-three patients satisfied the diagnostic criteria and were invited to participate in the study. Of those patients, 36 consented to undergoing intradiscal electrothermal coagulation. The control treatment consisted of an established physical therapy and rehabilitation program. The results of that study indicated that 60% of the selected patients experienced profound reductions in pain.⁴⁰ All of these studies indicate that, for carefully selected patients, intradiscal electrothermal annuloplasty seems promising, both as a technique to reduce chronic pain of discogenic origin and as an alternative to invasive spine surgery.

Spinal Endoscopy

In 1931, Burman⁴¹ introduced the concept of myeloscopy for direct spinal cord observation. In 1934, Mixter and Barr⁴² reported an open hemilaminectomy with intraoperative discotomy for treatment of intervertebral disk rupture into the spinal canal. In 1938, Pool⁴³ expanded on Burman’s work and reported myeloscopic inspection of the dorsal nerve roots of the cauda equina. In 1942, Pool⁴⁴ introduced the concept of intrathecal endoscopy and reported the results of more than 400 myeloscopic procedures.

Myeloscopy fell out of favor for a time because of the morbidity associated with insertion of a large-bore scope into the neural cavity. The state of spinal endoscopy remained essentially the same until Ooi et al⁴⁵ used an endoscope to examine the intrathecal space before surgery. Using improved technology, Ooi et al⁴⁶ were able to describe pathological features in greater detail, including chronic arachnoiditis and nerve root excursion during claudication associated with lumbar spinal stenosis.

Current FDA-approved indications for spinal endoscopy are documentation of pathological features and decompression of structures, direct nerve inspection, inspection of internal fixation, and delivery of therapeutic agents. The current uses of spinal endoscopy have been expanded to include closed decompression of spinal roots, use with lasers, epidural biopsies, percutaneous interbody fusion, and decompression of thoracic disk herniations. Spinal endoscopy has been used to perform thoracoscopy-assisted diskectomies, correction of kyphosis, biopsies, drainage of epidural abscesses, and disk space fusion. In addition, the uses of spinal endoscopy have been expanded to include laparoscopic techniques to treat such lumbar spine pathological conditions as lumbar diskectomy and fusion (anterior vs. posterior).

Lumbar Microendoscopic Diskectomy

MED to treat nerve root compression is a relatively new procedure that provides minimally invasive access to the spinal column. Medtronic Sofamor Danek (Memphis, TN) developed the instruments and technology (Figs. 1–9 and 1–10).

MED combines standard lumbar microsurgical techniques with endoscopy, enabling surgeons successfully to address free-fragment disk pathological factors and lateral recess stenosis. The endoscopic approach allows smaller incisions and less tissue trauma, compared with standard open microdiskectomy. Routine outpatient application and the avoidance of general anesthesia reduce hospital stays and costs.

FIGURE 1–9 Photograph of the microendoscopic diskectomy (MED) system: the set of dilators of incremental sizes, and the working channel used for MED.

Muramatsu et al47 reported on their series of 70 patients who underwent MED and 15 patients for whom Love’s method was used to treat lumbar disk disease. MED resulted in less blood loss (mean = 12.1 ml) than Love’s method (mean = 59.1 ml); analgesics (suppositories) were required by 52.0% of the MED-treated patients after surgery, whereas all of the patients treated with Love’s procedure required analgesics; and MED reduced the mean number of days before the patients became ambulatory (MED, 1.0 day; Love’s method, 4.9 days).

MED has the same indications as open microdiskectomy procedures. Muramatsu et al⁴⁷ did not use MED to treat patients with herniation associated with segmental instability and lower back pain, patients with combined lumbar canal stenosis and herniation, or patients who had previously undergone back surgery. Guiot et al⁴⁸ have shown the technical feasibility of percutaneous microendoscopic bilateral decompression of lumbar stenosis via a unilateral approach in a human cadaveric study.

Endoscopic Pedicle Screw Fixation of Lumbar Spine

The video-assisted posterolateral approach was developed by Boden and associates.⁴⁹ Posterior keyhole approaches for endoscopic placement of pedicle screws has been done using multiple portals or a single portal between the two pedicles. Muller et al⁵⁰ described the use of multiple portals in a cadaveric study to identify bony landmarks and to test the feasibility of performing endoscopic pedicle screw fixation. Endius (Plainville, MA) developed a system for a single portal approach for posterolateral transpedicular screw fixation and posterolateral lumbar arthrodesis (Fig. 1–11).

In both techniques, a transmuscular approach is performed to place the endoscope over the working area. A needle probe is positioned at the desired level, with biplanar fluoroscopic confirmation. Making a small skin incision around the probe, dilators of incremental size are passed over the probe until the desired blunt-tipped obdurator can be placed.

FIGURE 1–11 (A) The Endius system used in percutaneous transpedicular screw insertion. (B) Lateral and axial schematic representation of the Endius system used in transpedicular screw placement. The retractor system can be repositioned using the same entry point to obtain exposure for the adjacent pedicle.

Muller et al50 performed a transmuscular insertion of a pedicle screw-rod fixation device using a rigid operating sheath. This sheath (Thoracoport, AutoSuture Co., Norwalk, CT) measured 1.5 cm in diameter and 5 cm in length, and was used with a disposable trocar system consisting of a blunt-tipped obdurator, a threaded sleeve, and a shroud to secure the system. The surgical field was illuminated by an endoscope (Hopkins 11, Karl Storz GmbH & Co., Tuttlingen, Germany) with a diameter of 4 mm, a length of 18 cm, and angles of 0, 30, and 70 degrees. The Diapason pedicle probe (Stryker Instruments, Kalamazoo, MI) with a blunt tip was used to discover whether the pedicle walls were intact. The system has pedicle screws that have a U-shaped screw head.⁵⁰ The connecting rods are fixed in the screw heads via a ball-ring interface and are locked with locking screws. The pedicle screws are placed using an inclinometer, which provides the surgeon with instant feedback during the placement of pedicle screws.

The Endius system consists of similar dilators and probes. In addition, the Endius system has a fan apparatus that allows the surgeon to use blunt dissection techniques to visualize both pedicles and the interspace between them. Thus, this system accomplishes pedicle screw fixation of one motion segment with a single portal in each side. The visualization afforded is large enough to place pedicle screw constructs using rods/plates at the desired levels (Fig. 1–11).

Laparoscopic Lumbar Spine Surgery

The modern era of laparoscopy began in the 1980s, when Kurt Semm performed the first appendectomy in Germany. Semm, a physician and an engineer, developed many tools that are still in use. The first human laparoscopic cholecystectomy was performed in 1987 by DuBois et al.⁵¹ With the advantages of laparoscopic exposures being championed by urological, gynecological, and general surgeons, it is natural that spine surgeons would consider extending the advantages of laparoscopic exposures to the anterior lumbar spine. The significant advantages of transperitoneal laparoscopic surgical treatment include improved observation of surgical anatomic features, marked reductions in postoperative pain, early hospital discharges, and reduced incidence of postoperative ileus. In 1991, Obenchain⁵² reported the first use of a laparoscopic approach to the lumbar spine for a diskectomy (Fig. 1–12). Regan et al⁵³ described the technique and reported preliminary results for laparoscopic anterior lumbar fusion.

Gaur⁵⁴ was the first to describe an endoscopic retroperitoneal approach for urological procedures, which was later applied to treatment of the lumbar spine. Retroperitoneal, minimally invasive, endoscopic spine surgery has the advantage of not requiring carbon dioxide insufflation or entrance into the peritoneal cavity, and it avoids dissection near the large vessels and the hypogastric plexus. Advances in interbody fusion cage technology have generated a great deal of interest in laparoscopic techniques. Spinal fusion systems inserted with laparoscopic techniques maintain posterior loadbearing elements and reduce postoperative pain.

Since its introduction, transpedicular screw fixation has significantly changed the scope of spine surgery.55 Several complex spinal abnormalities, including neoplasms, degenerative diseases, trauma, and infections, are commonly treated with instrumentation to promote fusion via stabilization. The anatomic features of the diseased motion segments and the adjacent neural structures may be distorted and are often difficult to appreciate. Serious complications resulting from screw misplacement or pedicle cortex perforation can lead to devastating neurologic or vascular damage. Pedicle screw fixation provides the most stable construct. To increase the safety of the procedure, various methods have been used to target the pedicle better with respect to the trajectory and depth of screw placement. Most surgeons use assessments of anatomical landmarks, supplemented by fluoroscopy, to identify the anatomical features of the pedicles before placement of the pedicle screws. Weinstein et al⁵⁶ reported pedicle cortex violation in nearly 20% of cases.

Image guidance systems are widely used in intracranial surgery and have been adapted to assist with screw placement since the mid-1990s. The use of image guidance systems for pedicle screw placement has improved the accuracy of placement. The system relies on precise localization of the pedicles with CT. In addition, the transverse width, longitudinal depth, and trajectory angle can be measured (Fig. 1–13).

FIGURE 1–13 The virtual fluoroscopy system used for image-guided spinal surgery.

Nolte et al57 described the principles of computer-assisted pedicle screw fixation. The overall accuracy of their system was 1.74 mm, using CT scans with 2 mm image increments. Intraoperative surgical exposure of the posterior vertebral elements was performed using standard surgical techniques. An infrared camera (Optotrak; Northern Digital, Waterloo, Ontario, Canada) tracked specific instruments (i.e., pedicle probe, awl, and space pointer) equipped with light-emitting diodes. The dynamic reference was fixed to the spinous process of the vertebra to be instrumented. Normal bony landmarks and their correlations with the images confirmed the calibration accuracy. Using that computerized system, they reported a pedicle screw misplacement rate of 4.3% under clinical conditions.

Choi et al⁵⁸ reported the use of computer-assisted fluoroscopic targeting for pedicle screw fixation. They described a system in which the pedicle entry site and the depth of insertion were determined by intraoperative anteroposterior and lateral fluoroscopic scans. Those authors compared the accuracy of placement with the fluoroscopy-guided system versus the image guidance system and observed no significant differences.

Improved accuracy and ease of use with image guidance spine systems will facilitate localization of anatomical bony landmarks and expedite fixation for cervical, thoracic, and lumbar stabilization. With improvements in endoscopic and image-based guidance, the use of a combination of endoscopic and image guidance systems for thoracoscopic or laparoscopic stabilization procedures can be envisioned.

Vertebroplasty

The spine is composed of a rich trabecular lattice of cancellous bone encased in a hard cortical shell. Moreover, the spine is exposed to degrees of compressive loads and tensile stresses that are in symbiotic biomechanical play with the inner and outer matrixes of the vertebral bodies. Osteoporotic and neoplastic invasion of the vertebral bodies results in erosion of the cancellous network and development of vertebral compression fractures (VCFs), which can contribute to neurologic deficit, gross spinal instability, and ensuing deformity. Surgical management involves significant risks because all of these patients have significant comorbid conditions. It involves internal fixation using screws, plates, wires, cages, or rods and requires extensive surgical exposure. The time required for recuperation from open fixation procedures can be long. Obtaining satisfactory fixation in osteoporotic bone can be technically difficult, and the failure rate for spinal arthrodesis is significant.

Open procedures with the implementation of instrumentation were utilized in an attempt to establish pain control and address neurologic compromise. In an attempt to reduce such invasive operative treatment, percutaneous vertebroplasty (PVP) was developed in 1984 by Galibert and Deramond⁵⁹ in France as a minimally invasive outpatient procedure to offer immediate pain relief by the injection of polymethylmethacrylate (PMMA) bone cement into the vertebral body through a transpedicular percutaneous approach. Although a popular procedure in Europe, PVP was not performed in the United States until 1994.⁶⁰ This is currently used in the treatment of vertebral fractures involving osteoporosis, primary or secondary tumors of the spine, and spinal trauma.

Kyphoplasty

In an effort to reduce the high incidence of cement extravasation and detrimental sequelae, infection, cement toxicity, and adjacent fracture development due to an altered sagittal balance, kyphoplasty was developed in the mid-1990s by Dr. Mark Reiley. Kyphoplasty implements inflatable bone tamps inserted by a bilateral transpedicular approach that decreases intravertebral pressure and inserts PMMA into the cavity to elevate the vertebral end plates and restore vertebral height.⁶¹ The injection of highly viscous PMMA under lower pressures into a preformed cavity formed by the bone tamps greatly reduces the risk of extravertebral extravasation of the PMMA. Furthermore, kyphoplasty offers immediate pain relief, restores sagittal balance, enhances biomechanical regional milieu, improves vital capacity, thereby increasing mobility, and eradicates the detrimental psychological cascade that often affects patients with VCFs and an altered spinal alignment. In addition, the risk of subsequent vertebral fractures is decreased due to the restoration of the sagittal balance. Although PMMA has been successful in a slue of orthopedic and spine-related procedures, various bioactive substrates possessing osteoconductive and osteoinductive potential have been under investigation as alternatives to PMMA.

Endoscopic/Percutaneous Applications of Biological Agents

One of the many bioactive substrates under heated investigation are bone morphogenetic proteins (BMPs). These proteins, initially identified in 1965 by Urist,⁶² are multifunctional cytokines that function as osteoinductive agents in the formation of visceral development, cell proliferation and differentiation, and chondroblast and osteoblast formation. Recombinant BMPs promote and enhance solid fusion, obviate the need for autograft harvest and its associated morbidities, diminish the need for internal instrumentation, avoid reoperation rates associated with nonunions or implant failure, decrease hospital costs, and improve postoperative outcome. Early results, especially with BMP-2 and BMP-7, in animal models and in human subjects have been promising.^63,64 Furthermore, heated investigation of the vast potential of gene therapy is ongoing and motivated by the ability of direct application as well as prolonged and desired osteoinduction signaling.^65,66 Preliminary results have indicated the promotion of bone and intervertebral disk formation, as well as the encoding of various desired factors. The availability of these bone growth factors and gene therapy opens newer avenues for bone fusion by endoscopic or percutaneous methods to avoid the morbidity and risks associated with fusion by open methods.

The field of spine surgery has been witness to immeasurable growth in the past four decades. The evolution of surgical techniques and treatment methodologies is testament to the optimal quality of care each physician seeks to offer the patient. Although there has been an inclination toward more minimally invasive techniques in spine surgery, indications and proper patient selection are essential pragmatic dogmas that must be employed in consideration of an operative treatment modality to obtain optimal clinical outcome and patient satisfaction.

1. Detmer DE, Buchanan-Davidson DJ. Ambulatory surgery. In: Rutknow IM, ed. Socioeconomics of Surgery. St. Louis: CV Mosby; 1989:30–50.

2. Lang JK, Kolenda H. First appearance and sense of the term “spinal column” in ancient Egypt. J Neurosurg. 2002;97:152–155.

3. Marketos SG, Skiadas P. Hippocrates: the father of spine surgery. Spine. 1999;24:1381–1387.

4. Knoeller SM, Seifried C. History of spine surgery. Spine. 2000;25: 2838–2843.

5. Fang HSY Ong GB. Direct anterior approach to the upper cervical spine. J Bone Joint Surg Am. 1962;44A:1588–1604.

6. Frempong-Boadu AK, Faunce WA, Fessler RG. Endoscopically assisted transoral-transpharyngeal approach to the craniovertebral junction. Neurosurgery. 2002;51:60–66.

7. Scoville WB, Whitcomb BB. Lateral rupture of cervical intervertebral discs. Postgrad Med. 1966;39:174–180.

8. Roh SW, Kim DH, Cardoso AC, Fessler RG. Endoscopic foraminotomy using MED system in cadaveric specimens. Spine. 2000;25: 260–264.

9. Jacobaeus HC. Possibility of the use of cystoscope for investigation of serious cavities. Munch Med Wochenschr. 1910;57:2090–2092.

10. Jacobaeus HC. The practical importance of thoracoscopy in surgery of the chest. Surg Gynecol Obstet. 1921;32:493–500.

11. Mack MJ, Regan JJ, Bobechko WP, et al. Application of thorascopy for diseases of the spine. Ann Thorac Surg. 1993;56:736–738.

12. Rosenthal DJ, Rosenthal DR, Simone A. Removal of a protruded thoracic disc using microsurgical endoscopy: a new technique. Spine. 1994;19:1087–1091.

13. Jho HD. Endoscopic microscopic transpedicular thoracic discectomy: technical note. J Neurosurg. 1997;87:125–129.

14. Chiu J, Clifford T. Microdecompressive percutaneous discectomy: spinal discectomy with new laser thermodiskoplasty for nonextruded herniated nucleus pulposus. Surg Technol Int. 1999;8:343–351.

15. Jansen EF, Balls AK. Chymopapain: a new crystalline proteinase from papaya latex. J Biol Chem. 1941;137:459–460.

16. Thomas L. Reversible collapse of rabbit ears after intravenous papain and prevention of recovery by cortisone. J Exp Med. 1956; 104:245–252.

17. Smith L, Garvin PJ, Jennings RB, Gesler RM. Enzvme dissolution of the nucleus pulposus. Nature. 1963;198:1311–1312.

18. Nordby EJ, Javid MJ. Continuing experience with chemonucleolysis. Mt Sinai J Med. 2000;67:311–313.

19. Nordbv EJ, Brown MD. Present status of chymopapain and chemonucleolysis. Clin Orthop. 1977;129:79–83.

20. Nordby EJ, Lucas GL. A comparative analysis of lumbar disk disease treated by laminectomy or chemonucleolysis. Clin Orthop. 1973;90: 119–129.

21. Lorenz M, McCulloch J. Chemonucleolysis for herniated nucleus pulposus in adolescents. J Bone Joint Surg Am. 1985;67A:1402–1404.

22. Nordby EJ, Wright PH, Schofield SR. Safety of chemonucleolysis: adverse effects reported in the United States, 1982–1991. Clin Orthop. 1993;293:122–134.

23. Ramirez LF, David MJ. Cost effectiveness of chemonucleolysis versus laminectomy in the treatment of herniated nucleus pulposus. Spine. 1985;10:363–367.

24. Hijikata S, Yamagishi M, Nakayama T, Oomori K. Percutaneous diskectomy: a new treatment method for lumbar disc herniation. J Toden Hosp. 1975;39:5–13.

25. Kambin P, Gellman H. Percutaneous lateral discectomy of the lumbar spine: a preliminary report. Clin Orthop. 1983;174:127–132.

26. Onik G, Helms CA, Ginsberg L, Hoagland FT, Morris J. Percutaneous lumbar diskectomy using a new aspiration probe: porcine and cadaver model. Radiology. 1985;155:251–252.

27. Kambin P, Sampson S. Posterolateral percutaneous suction-excision of herniated lumbar intervertebral discs: report of interim results. Clin Orthop. 1986;207:37–43.

28. Ascher PW, Heppner F. CO₂-laser in neurosurgery. Neurosurg Rev. 1984;7:123–133.

29. Ascher PW. Status quo and new horizons of laser therapy in neurosurgery. Lasers Surg Med. 1985;5:499–506.

30. Choy DS, Case RB, Fielding W, Hughes J, Liebler W, Ascher P. Percutaneous laser nucleolysis of lumbar disks. N Engl J Med. 1987; 317:771–772.

31. Yonezawa T, Onomura T, Kosaka R, et al. The system and procedures of percutaneous intradiscal laser nucleotomy. Spine. 1990; 15:1175–1185.

32. Davis JK. Percutaneous discectomy improved with KTP laser. Clin Laser Mon. 1990;8:105–106.

33. Yeung AT. Consideration for the use of the KTP laser for disc decompression and ablation. In: Sherk HIT, ed. Spine: State of the Art Reviews—Laser Discectomy. Philadelphia: Hanley & Belfus;1993:67–93.

34. Choy DS, Ascher PW, Saddekni S. Percutaneous laser disc decompression. Spine. 1992;17:949–956.

35. Davis JK. Early experience with laser disc decompression: a percutaneous method. J Fla Med Assoc. 1992;79:37–39.

36. Ottolenghi CE, Argentina PA. Diagnosis of orthopaedic lesions by aspiration biopsy: results of 1061 punctures. J Bone Joint Surg Am. 1955;37A:443–464.

37. Craig FS. Vertebral body biopsy. J Bone Joint Surg Am. 1956;38A: 93–102.

38. Kambin P. Arthroscopic microdiscectomy. Arthroscopy. 1992;8: 287–295.

39. Mayer HM, Brock M. Percutaneous endoscopic discectomy: surgical technique and preliminary results compared to microsurgical discectomy. J Neurosurg. 1993;78:216–225.

40. Saal JA, Saal JS. Intradiscal electrothermal treatment for chronic discogenic low back pain: a prospective outcome study with minimum 1-year follow-up. Spine. 2000;25:2622–2627.

41. Burman MS. Myeloscopy or the direct visualization of the spinal cord and its contents. J Bone Joint Surg. 1931;13:695–696.

42. Mixter WJ, Barr JS. Rupture of intervertebral disc with involvement of spinal canal. N Engl J Med. 1934;211:210–215.

43. Pool JL. Direct visualization of dorsal nerve roots of the cauda equina by means of a myeloscope. Arch Neurol Psychiatr. 1938;39: 1308–1312.

44. Pool JL. Myeloscopy: intraspinal endoscopy. Surgery. 1942;11: 169–182.

45. Ooi Y Sato Y, Mikanagi K, Morisaki N. [Myeloscopy.] No To Shinkei. 1977;29:569–574.

46. Ooi Y, Sato Y, Morisaki N. Myeloscopy: the possibility of observing the lumbar intrathecal space by use of an endoscope. Endoscopy. 1973;5:901–906.

47. Muramatsu K, Hachiya Y Morita C. Postoperative magnetic resonance imaging of lumbar disc herniation: comparison of microendoscopic discectomy and Love’s method. Spine. 2001;26:1599–1605.

48. Guiot BH, Khoo LT, Fessler RG. A minimally invasive technique for decompression of the lumbar spine. Spine. 2002;27:432–438.

49. Boden SD, Moskovitz PA, Morone MA, Torihitake Y. Video-assisted lateral intertransverse process arthrodesis: validation of a new minimally invasive lumbar spinal fusion technique in the rabbit and nonhuman primate (Rhesus) models. Spine. 1996;21:2689–2697.

50. Muller A, Gall C, Marz U, Reulen HJ. A keyhole approach for endoscopically assisted pedicle screw fixation in lumbar spine instability. Neurosurgery. 2000;47:85–96.

51. Dubois F, Icard P, Berthelot G, Levard H. Coelioscopic cholecystectomy: preliminary report of 36 cases. Ann Surg. 1990;211:60–62.

52. Obenchain TG. Laparoscopic lumbar discectomy. J Laparoendosc Surg. 1991;1:145–149.

53. Regan JJ, McAfee PC, Guyer RD, Aronoff RJ. Laparoscopic fusion of the lumbar spine in a multicenter series of the first 34 consecutive patients. Surg Laparosc Endosc. 1996;6:459–468.

54. Gaur DD. Laparoscopic operative retroperitoneoscopy: use of a new device. J Urol. 1992;148:1137–1139.

55. Roy-Camille R, Saillant G, Berteaux D, Marie-Anne S, Mamoudy P. Vertebral osteosynthesis using metal plates: its different uses. Chirurgie. 1979;105:597–603.

56. Weinstein JN, Spratt KF, Spengler D, Brick C, Reid S. Spinal pedicle fixation: reliability and validity of roentgenogram-based assessment and surgical factors on successful screw placement. Spine. 1988;13:1012–1018.

57. Nolte LP, Zamorano LJ, Jiang Z, Wang Q Langlotz F, Berlemann L. Image-guided insertion of transpedicular screws: a laboratory set-up. Spine. 1995;20:497–500.

58. Choi WW, Green BA, Levi AD. Computer-assisted fluoroscopic targeting system for pedicle screw insertion. Neurosurgery. 2000;47: 872–878.

59. Galibert P, Deramond H. La vertebroplastie percutanée comme traitement des angiomas vertebraux et des affections dolorigenes et fragilisantes du rachis. Chirurgie. 1990;116:326–335.

60. Barr JD, Barr MS, Lemley TJ, McCann RM. Percutaneous vertebroplasty for pain relief and spinal stabilization. Spine. 2000;25: 923–928.

61. Dudeney S, Lieberman IH, Reinhardt MK, Hussein M. Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma. J Clin Oncol. 2002;20:2382–2387.

62. Urist M. Bone formation by autoinduction. Science. 1965;150: 893–899.

63. Boden SD, Martin GJ Jr, Horton WC, et al. Laparoscopic anterior spinal arthrodesis with rhBMP-2 in a titanium interbody threaded cage. J Spinal Disord. 1998;11:95–101.

64. Boden SD, Hair GA, Viggeswarapu M, Liu Y Titus L. Gene therapy for spine fusion. Clin Orthop. 2000;379(suppl):S225–S233.

65. Cha CW, Boden SD. Gene therapy applications for spine fusion. Spine. 2003;28(suppl):S74–84

66. Alden TD, Pittman DD, Beres EJ, Hankins GR, Kallmes DF, Wisotsky BM, Kerns KM, Helm GA. Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy. J Neurosurg. 1999;90 (suppl):109–114