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Laurance Johnston, Ph.D.

Sponsor: Institute of Spinal Cord Injury, Iceland



1) Dr. Carlos Lima (Portugal)

2) Dr. Hongyun Huang (China)

3) Dr. Alan MacKay-Sim (Australia)

4) Dr. Tiansheng Sun (China)

5) Dr. Wlodzimierz Jarmundowicz & Dr. Pawel Tabakow (Poland)

1) Dr. Carlos Lima (deceased 2012) and colleagues (Lisbon, Portugal and other countries) implant whole olfactory tissue obtained from the patient (i.e., no immunological rejection) back into the injury site (click on illustration) (J Spinal Cord Med 29(3), 2006). Lima believes that more than one cell type is needed to maximize regeneration, including not only OECs but also olfactory neurons in different developmental stages, and precursor stem cells.

In Portugal, Lima's team has treated 120+ patients from throughout the world, including from the USA (53), Portugal (21), Italy (11), Canada (3), UK (3), and other countries (10). Fourteen patients have also been treated in Columbia, seven in Greece, and six in Saudi Arabia. In addition, new treatment centers are being planned in Japan, India, and New Zealand (September 2006 update). Purportedly, many of the patients have accrued significant benefit.

Lima’s work was featured on an award-winning PBS documentary entitled “Miracle Cells.” In 2005, the World Technology Network named Lima as a finalist for a prestigious innovation award in health and medicine.

The surgery’s critical procedure is the collection of about one fourth of the patient’s olfactory tissue through unique procedures that maximize the harvesting of that tissue and minimize the collection of closely associated nasal respiratory tissue. Although Lima’s experience indicates that small amounts of contaminating respiratory tissue are innocuous, it nevertheless lacks olfactory tissue’s regenerative components. Because olfactory tissue can diminish over time, patient age is important, and as a result, he usually does not accept patients older than 40. Patients regain smelling ability within several weeks.

The injury site is exposed with a laminectomy and then myelotomy (cutting open the cord’s membrane coverings). Although it is impossible to remove all of the scar tissue at the injury site cavity, the scar’s top and bottom stumps are taken off so that the cord is visible, and in between, holes are made in the scar.

The isolated olfactory tissue is dissected into small pieces while it is immersed in a small amount of the patient’s cerebrospinal fluid. The pieces are then implanted into the cavity. Lima estimates that a 1-cm2 cavity filled by this tissue will contain approximately 400,000 stem cells and 4 million each of mature neurons, immature neurons, and other supporting cells.

Lima believes maximal restored function will require aggressive rehabilitation. To separate the function-restoring effects of such physical rehabilitation with the procedure itself, many of the more recent patients have been required to initiate physical rehabilitation before the surgery and not just afterwards. For example, the Detroit Medical School has developed an intense rehabilitation program that has treated 34 patients who have undergone olfactory-tissue program.

A number of articles published in professional journals have focused on Lima’s procedures, including the following:

1) In 2006, Lima’s team reported the results of transplanting olfactory tissue into the injury site of seven patients with SCI over the July 2001 to March 2003 period. These patients were among the initial ones treated with Lima’s procedures.

Four patients were men, and three were women. Their age ranged from 18 to 32 (average 23) years, and the time since injury varied from 0.5 to 6.5 years. The spinal cord injury site ranged from the cervical C4 to thoracic T6 level. All patients had been injured from road accidents, except one who was injured from a fall. Using the ASIA-impairment scale (American Spinal Injury Association – see appendix), in which grade A corresponds to a complete injury and grade E corresponds to recovery, all patients had grade-A injuries before transplantation. The length of the injury-site lesion ranged from one to six centimeters (2.4 inches).

Post-procedure magnetic resonance imaging (MRI) indicated a complete filling of the lesion sites except for the patient with the largest, six-centimeter lesion. Eighteen months after injury, all patients demonstrated varying degrees of improvement in either sensation or motor function in paralysis-affected muscles. Two improved from ASIA-grade-A (complete) to ASIA-grade-C (incomplete) injuries. One patient lost some sensation but gained motor function and believed that the trade-off was worth it.

Electrophysiological evaluations of nerve conduction indicated that three patients could voluntary control muscles that they were unable to do so before the procedure. One patient reported the return of bowel control, and two patients recovered sufficient bladder sensation to allow a discontinuation of catheterization.

Although the procedure involved the removal of a portion of the subject’s olfactory tissue for transplantation into the injury site, all subjects eventually recovered normal smelling capability within three months.

2) In a 2009 article, Lima’s team reported the results of a more comprehensive study which transplanted olfactory tissue into 20 patients followed by extended, aggressive physical rehabilitation. Recruited between April 2003 and December 2006, these patients were different from the ones recruited in the previous study. The investigators hypothesized that three treatment components are critical for functional improvement: 1) transplanting stem-cell-containing olfactory-tissue (i.e., not just olfactory ensheathing cells), 2) cleaning out injury-site scar tissue to make room for transplanted tissue and to remove regeneration barriers, and 3) intense rehabilitation.

Patients were required to carry out extensive physical rehabilitation both before and after transplantation. Because there is an understandable desire to maximize the functional benefits after any cell-transplantation procedure, subjects tend to rehabilitate much more aggressively after transplantation than before. By so doing, it becomes difficult to attribute any restored function to merely the transplantation. In other words, improvement may be just due to a now highly motivated individual doing a lot of physical rehabilitation.

Subject Characteristics: Seventeen men and three women were enrolled into the study. Age ranged from 19 to 37 (average 30) years. The time lapsing from injury to transplantation varied from 1.5 to ~16 years; in other word, all subjects had chronic injuries. With such injuries, relatively little additional recovery is spontaneously expected, and, as such, any improvement is most likely due to the intervention. Injuries were sustained from traffic (14), sports (4), and work accidents (2). Thirteen subjects had cervical injuries ranging from the C4 to C8 level, and seven had thoracic injuries ranging from the T5 to T12 level.

Fifteen subjects had grade A (sensory and motor complete) and five grade B (motor complete) injuries at the time of transplantation. Because the injury-site scar tissue is removed as a part of the procedure, all lesions had to be less than three centimeters (~1.2 inches) in length for cervical injuries and four centimeters for thoracic injuries.

Physical Rehabilitation: Subjects averaged 32-hours per week rehabilitation for 35 weeks before transplantation; and postoperative rehabilitation averaged 33 hours per week for 92 weeks. Rehabilitation was undertaken at three centers, two in Portugal and one in Italy. One center used robotic bodyweight-supported treadmill training (see discussion under “Treadmill Rehabilitation Programs”), and the other used an assisted over-ground walking training with weight bearing on the hips and feet to promote sensory and muscle-movement feedback. Results indicated that the latter approach was much more effective in promoting functional improvement after transplantation. The investigators now believe that this method allows the movement freedom to promote the development of new movement patterns that may enhance functional connections.

Results: Various functional status assessments were carried out before transplantation (i.e., baseline) and periodically afterwards. Average duration of follow-up was 28 months.

A) Impairment Scales: Using ASIA-impairment evaluations, 11 of the 20 subjects improved one grade or more. Specifically, six improved from grade A (complete injury) to grade C (regaining some sensation and motor function), three from grade B to C, and two from grade A to B (i.e., recovery of some sensation).  Although there was considerable patient variability, motor-function, light-touch, and pin-prick scores all improved on average.

B) Walking: Thirteen subjects from two of the three study centers were evaluated for ambulatory improvements using the “Walking Index for Spinal Cord Injury” (WISCI), a measurement which assesses the amount of assistance required for ambulation. All 13 demonstrated some improvement using this evaluation, one progressing from no mobility to walking 10 meters with braces and crutches.

C) Functional Independence:  The same 13 subjects were also evaluated for their ability to carry out various activities of daily living and self care (e.g., eating, grooming, bathing, etc) by using of the FIM scale (Functional Independence Measure). The scale is a predictor of the amount of assistance or adaptive equipment an individual may need in everyday life. All subjects improved their FIM scores after the transplantation-rehabilitation intervention.

D) Anal Assessment:  Of the 15 subjects without anal sensation at the baseline evaluation, nine recovered some feeling. Before the intervention, all 20 subjects were unable to contract their anus, an ability recovered by five afterwards.

E) Bladder Function: Of the 15 patients without bladder sensation at the baseline evaluation, five regained the ability to sense bladder fullness. One patient recovered bladder control.

F) Nerve Conduction: Electrophysiological evaluations of nerve conduction indicated that 15 subjects could direct signals to previously paralyzed muscles.

Side Effects: Like the earlier study, all subjects eventually recovered smelling ability. One patient developed meningitis two weeks after surgery and, as a result, lost sensory and motor function, some of which came back over time. The investigators suspected that the infection was caused when the extracted olfactory-tissue sample was withdrawn through the nasal passages.

Conclusion: The investigators concluded that olfactory-tissue transplantation is “feasible, relatively safe, and possibly beneficial in people with chronic SCI when combined with postoperative rehabilitation.” They also emphasized that neither rehabilitation nor transplantation alone is sufficient to promote recovery; both are needed. The results also suggest that the nature of the post-transplantation rehabilitation is extraordinarily important.

3) A 2009 article coauthored by Indian scientists trained by Lima’s team as well as himself reported the results of an Indian pilot study, which treated five men with chronic thoracic (4) or cervical injuries (1) over the November 2006 to January 2008 period.  Patient age ranged from 18 to 40 years, and the time lapsing since injury varied from 2.4 to 8.2 years. Various follow-up assessments similar to those described in the previous study were carried out before transplantation and afterwards at half-year intervals up to 18 months, although one patient just had a six-month assessment at the time the article was submitted.

Unlike the previous study, functional improvements were generally not observed. The investigators specifically concluded that although the procedure is relatively safe and feasible, no “efficacy could be demonstrated which could be attributed to the procedure.”

In the previous article, Lima implied that this Indian pilot study may have failed to generate functional improvements because the study’s post-transplantation rehabilitation program, which he believes is extraordinarily important, was ambiguously implemented. Specifically, he notes that patients were only given instructions to follow a rehabilitation program at home, and their compliance with it and its intensity is unknown.

Clearly, when it comes to this olfactory-tissue approach for restoring function after SCI, the nature, intensity, and duration of the post-transplantation rehabilitation program will be one of those extremely important, “God-is-in-the-details” factors that determines whether success is forthcoming or not.

2) Dr. Hongyun Huang (China) has transplanted olfactory ensheathing cells (OECs) isolated from fetal olfactory bulbs into more than 1,200 patients from 70+ countries with a variety of neurological disorders, including 600+ with chronic SCI. The OECs were isolated from 12-16-week aborted fetuses, and grown and expanded in culture for 12-17 days. For SCI, about a million cells were injected around the injury site exposed through a limited laminectomy. The OECs were often transplanted many years after injury.

Because many patients regain some function soon after surgery, improvement is not due to relatively slow neuronal regeneration or remyelination. Huang speculates that OECs wakeup quiescent neurons that still transverse the injury site, perhaps by altering the injury site’s environment through secreting growth factors and producing adhesion and matrix molecules.

Huang’s SCI work has been summarized in several professional articles. In 2003 and 2006 articles, he reported the results of transplanting OECs into 139 men and 32 women, of which 114 were quadriplegics and 57 paraplegics. Ages ranged from 2 to 64 (average 35) years, and the interval between injury and admission varied from 6 months to18 years. To ensure that improvement was not merely due to surgery-associated decompression, patient MRIs had to indicate the absence of compression before surgery. In addition, the cord had to have some structural continuity through the injury site, the situation for most individuals with SCI.

Function was assessed before and 2-8 weeks after surgery using the ASIA (American Spinal Injury Association) impairment scales, which include motor-function, light-touch, and pin-prick scores. Improvement was noted for each of these scores in five age categories (<20, 21-30, 31- 40, 41- 50, and >50).

Another study evaluated the influence of various factors (e.g., age, sex, time from injury, completeness of injury, and injury level) on OEC-transplantation effectiveness in 300 patients with chronic injuries. Once again, most patients demonstrated some motor and sensory improvement. Those with cervical injuries recovered more function than those with thoracic injuries. No differences were noted among the other injury factors examined.

In 2007, Huang reported the results of following 16 OEC recipients (14 men, 2 women) with MRI imaging for an average of 38 months (6). Ten and six had complete and incomplete injuries, respectively.  The time elapsing from injury ranged from 22 to 55 years. The MRI follow-up imaging of the cord showed the absence of tumors, new or expanding cysts, infection, or neural disruption at the transplantation site, findings which supported the procedure’s safety.

In 2012, Huang and his colleagues summarized the long-term outcomes of treating 108 patients with complete chronic injuries with OEC transplantation. Eight-four patients were men, and 24 were women; age ranged from 6 to 58 (average 34), and the time injured before treatment varied from 0.5 to 30 (average 3.5) years. Fifty-one, 42, and 15 had cervical, thoracic, and thoracocolumbar junction (T12-L1) injuries, respectively. After transplantation, patients were followed for an average of 3.5 years, using a variety of assessments, including the the ASIA impairment scales and its component motor-function, light-touch, and pin-prick scores. Similar to the aforementioned short-term results, modest improvements were noted on average for each of these scores. Fourteen of the 108 patients improved from ASIA-A (complete injury) to ASIA-B (some sensory return), and 18 improved from ASIA-A to ASIA-C (some sensory and motor function recovery). Nine patients regained limited ambulatory ability, and 12 of the 84 men had improved sexual functioning. In general, patients who pursued aggressived rehabilitation obtained better results.

3) Dr. Alan Mackay-Sim’s team (Brisbane, Australia), in a single-blind phase-1 clinical trial, has implanted autologous OECs back into the patient’s injured cord (Brain, published online October 11, 2005). The OECs were isolated from the patient’s nasal tissue and amplified in culture to yield up to 20-million cells over six weeks.  These cells were injected into 40 sites surrounding the injury site. The progress of three male subjects (18-55 years of age) with complete thoracic injuries sustained 6-32 months previously who received OEC transplants were compared to three individuals who did not have the transplants. These comparative assessments were blinded, i.e., progress-monitoring assessors do not know which patients had the procedure. These periodic assessments included MRI, neurological, psychosocial, ASIA (American Spinal Injury Association), and FIM (Functional Independence Measure) evaluations. The investigators concluded “transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to one year post-implantation.”

In 2008, the results of three-years of follow-up experience were reported. Again, no adverse effects were observed from the OEC-transplantation procedures. For example, no tumors were observed nor the development of syringomyelia cysts within the cord (see glossary). In one patient, improvement was noted in light-touch and pin-prick sensitivity. The investigators emphasized that it was important not to over-extrapolate the findings due to the small number of patients involved in this preliminary trial.


4)Using the procedures developed by Dr. Huang described above,  Dr. Tiansheng Sun and colleagues (China) reported the transplantation of fetal OECs into 11 patients with complete, chronic SCI (13-14). Nine were men and two were women; age varied from 25 to 55 years; and the interval between injury and transplantation ranged from 2 to 5.5 years. After exposing the cord with a laminectomy, approximately 500,000 cells suspended in 0.5 milliliters were injected at various locations surrounding the injury site.  There were no procedural complications. Patients were followed for an average of 14 months. Although locomotor improvement was minimal, sensation improved moderately as measured by ASIA evaluations, and a number of patients had less spasticity.

5) Dr. Wlodzimierz Jarmundowicz, Dr. Pawel Tabakow, and colleagues (Poland) have initiated a phase-I clinical trial to assess the safety and feasibility of transplanting autologous OECs (i.e., obtained from the patient) to treat complete SCI. The procedures were developed on a foundation of preliminary studies using rats and human cadavers. The first operation was performed in June 2008 on a 27-year-old male who sustained a complete (ASIA-A), thoracic T10-11 injury four years earlier from a knife wound.

OECs were isolated from the patient’s olfactory tissue and grown and amplified in culture. Three weeks later, the spinal-cord injury area was exposed through a two-level laminectomy, fibrous adhesions were removed, and a cell suspension of OECs and olfactory fibroblasts were microinjected ~120 times into the area surrounding the injury site. Each injection contained ~25,000 cells. Four weeks after the operation, there were no adverse effects attributed to the procedures. The patient continues neurorehabilitation.

A second patient was similarly treated in August 2008. This individual was a 27-year old male who sustained a thoracic T6-7, ASIA-A-complete injury five years earlier.  After the cells were cultured for 17 days, they were reintroduced into the patient’s spinal cord. No adverse complications were noted in the month following transplantation.

One-year follow-up of these patients indicated that 1) the OEC transplantation was safe and 2) both patients had improved neurologically. Specifically, the first patient improved from an ASIA-A (motor and sensory complete injury) to an ASIA-C incomplete injury; and the second patient improved from ASIA A to ASIA B (i.e., some restored sensation). In contrast, no control patients have showed improvement.

In June 2010, a third patient, a 26-year-old male with a complete thoracic T4 injury, was treated in a similar fashion.

A 2013 article provided more in-depth information on the procedures used in these three patients, as well as the outcomes observed one year after transplantation. To ensure that any improvement was not merely the result of physical rehabilitation, all patients underwent extensive physical rehabilitation before and after transplantation. Outcomes were compared to those of three comparably injured subjects, who did not have the procedure but underwent physical rehabilitation. One year after transplantation, no adverse effects were observed. Two of the three transplantation patients improved from ASIA A to ASIA C, and although the third patient remained at the ASIA-A level, some motor and sensory improvement accrued.  No neurological improvement was observed in control subjects.

In 2014, the investigative team reported the transplantation of olfactory cells obtained not from the patient’s more accessible olfactory mucosal tissue (i.e., nose) but from an olfactory bulb located under the brain’s cranium. The 38-year-old male patient had sustained an ASIA-A complete injury at the thoracic T-9 level 13 months before the procedure due to a knife assault. The injury had resulted in an eight-millimeter gap in the spinal cord, the stumps being connected by a thin rim of spared tissue. An olfactory bulb was obtained through a craniotomy, a surgical procedure that opens up the skull to access the brain. The bulb was cultured to obtain a mixture of OECs and olfactory nerve fibroblasts. After exposing the spinal cord injury-site, scar and tethering tissue were removed, followed by injection of the cultured cells into multiple locations surrounding the injury site. Finally, four sural-nerve strips obtained from the patient’s leg were used to bridge the spinal cord stumps. The surgery was followed by extended, aggressive physical rehabilitation. To ensure that any functional improvement was not merely due to aggressive rehabilitation that had been done after but not before surgery, the patient underwent similar rehabilitation for eight-months before the intervention. No neurological improvement accrued during the pre-surgical period.

In the 19-month follow-up period, the patient improved from an ASIA-A motor-and-sensory-complete injury to an ASIA-C incomplete injury. This upgrading correlated with improved trunk stability, recovery of some sensation and voluntary lower-extremity movements, and increased muscle mass. In addition, imaging assessments demonstrated that the nerve grafts had bridged the gap at the spinal cord injury site. Noting that it was difficult to determine the contribution of each element of this multi-pronged intervention to (i.e., untethering and scar removal, cell transplantation, sural-nerve bridging, and physical rehabilitation), the investigators believed that all components collectively contributed to the patient’s neurological improvement.