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Tag: stem cell therapy

Stem Cell Therapy in Urethral Stricture Disease; a Concept

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Regenerative medicine is a relatively young field in the treatment of various conditions. Several novel applications of various types of stem cells have been tried and applied in various aspects of urology. Some published articles provide promising early results.
 
There are two main sources of stem cells. These are embryonic stem cells (ESCs) and adult-derived stem cells (ADSC). The latter has many sources including bone marrow stem cells (BMSCs), skeletal-muscle-derived stem cells (SkMSCs), adipose-tissue-derived stem cells (ADSCs), and arguably, amniotic-fluid-derived stem cells (AFSCs).
 
Stem cell use in urology:
 
BMSCs, SkMSCs, and AFSCs have been used for bladder augmentation and detrusor regeneration in animals. SkMSCs are the only stem cells to have been successfully tested in humans, for the treatment of stress urinary incontinence. ESCs, BMSCs, and SkMSCs have been shown to improve erectile function in animal models. Both ESCs and BMSCs can be differentiated into sperm and, remarkably, the ESC-derived sperms have generated offspring in mice.
 
Adipose-derived stem cells:
 
ADSC research is a relatively young field, and these cells are largely unstudied in urology. However, as a result of their high differentiation potential and ease of isolation, ADSCs represent an exciting resource for tissue engineering and regenerative medicine within and beyond urology.
 
Male urethral stricture disease:
 
This is one of the common urological conditions mainly affecting young men, and occasionally older men. The main causes are inflammatory from recurrent urethritis and urethral injury, whether from an accident or iatrogenic.
 
Until recently, the treatment of urethral stricture is mainly surgical, starting from endoscopic dilatation or urethrotomy, both have a high risk of recurrence, starting from 50% with increasing failure of cure in recurrent ones. Several attempts have been made to combat this problem. Many use intermittent dilatation, that though keeps the uretha patent, it induces more inflammatory reactions from repetitive trauma. The other way is major surgery, called urethroplasty, with a higher success rate but comes at a higher price of complications list (such as infection, bleeding, penile curvature, sexual dysfunction, and of course, recurrence of the stricture).
 
The main reason for the failure of urethral dilatations is the inflammatory reaction generated by the procedure, with resulting fibrosis.
 
This where stem cell therapy comes into place. Stem cells provide an alternative way of healing. Once deployed in the area of injury, they differentiate into the local functional cells (in this case the urothelium and possibly, in dense strictures, spongial tissue). This has the potential to prevent the usual inflammatory process that follows trauma, with potentially less scarring.

 Hypothesis:
 
Stem cells, once applied to the area of urethra dilatation/urethrotomy, in the same operative setting, might increase the chance of success of the operation, obviating the need for repetitive endoscopic dilatations and even urethroplasty.

Study proposal and methods:
 
A prospective randomized double blinded study is proposed, aiming at recruiting 40 participants;
 

  • Group I: n=20 who would receive the conventional urethral dilatation/optical urethrotomy. In addition, they would receive ADSC.
  • Group II: n=20 would receive the conventional urethral dilatation/optical urethrotomy.
     
    Procedure (Group I):
     
    Under general anaesthesia (whilst having the urethral dilatation). ADSC will be harvested by liposuction from the abdominal fat using micro-cannula and two tiny abdominal wall incisions. This fat would be then treated for mechanical extraction of the stem cells using purposely made nano blades. The process would take an extra half-an-hour to prepare. The resultant fluid containing stem cells would be then injected via the cystoscope into the area of the urethral dilatation/urethrotomy.

Post-operative care:
 
Both groups will have the same post-operative protocol; mainly having a urethral catheter, that will remain in situ from several hours up to 5 days depending on the density of the urethral stricture.
 
Follow up:
 
Anonymized and coded participants in both groups will have their first post-operative follow-up with an independent and “blinded” clinician, in two weeks, one month, three months, six months, and one year respectively. The follow-up will entail clinical assessment along with UroFlow rate measurement.
 
Results:
 
Once analyzed, the results will be written, presented at conferences, and will be published.
 

Summary:

The future of medicine ( and I dare to say that the possible demise of surgery!) lies in the development and application of stem cells to treat and possibly cure patients with various conditions.

However, as exciting as it seems, this application is quite novel, at least in many medical and surgical specialities, and it’s the application will have to be carried out within a reach, ethics, and Governance framework.

Once properly applied, the prospects are endless

Extra Caporal Shockwave Treatment plus Regenerative Medicine and Treating a Male Sexual Dysfunction: An update

Posted on by Dr. Ali Thwaini

Male sexual dysfunction is an increasing modern life condition with more than 40% of men being affected as age of 40. This is further complicated by the increasing prevalence of metabolic syndrome and the sedentary lifestyle. This has led to ever increasing incidence of atherosclerosis hyperlipidemia and type two diabetes.

Natural Cures for Erectile Dysfunction

In addition to the importance of the emphasis on improving the lifestyle measures and treating a male sexual dysfunction(Mainly in the form of exercise stopping smoking minimizing the alcohol intake and adopting healthy diet), Other medications seem to help Though on a temporary basis.

Recently there has been increasing interest and more permanent and as close to natural as possible solutions for male sexual dysfunction. Below are some of them:

Low-Intensity Extracorporeal Shock Wave Therapy

LiESWT:Shockwave therapy was introduced since the early 80s with the first experience being targeted towards kidney stones. However, recently, studies have shown that microtrauma and used by shockwaves would lead to an acute inflammatory reaction of the effect of tissues with the resultant stimulation of the healing process towards normality.

This would theoretically stimulate the growth and development of small blood vessels with the resultant increase blood flow to the affected area. This has been adopted and treatment of cardiovascular diseases and other several musculoskeletal conditions.

Urology, being at the forefront of other specialties, has adopted this method and treating various mail conditions including Peyronie’s disease and Erectile dysfunction.

Although shockwave treatment as monotherapy has now been adopted at the Urology guidelines its results are marginally encouraging With an estimated success rate of around 70%. The treatment is fairly simple considering 2 to 3 weekly attendances is at the clinic with a 15-minute session per visit for up to six weeks and the results are expected between three and six months

Platelet-rich plasma cells

Another recently adopted treatment for a variety of medical conditions mainly cosmetic with the principle of using the patients’ own fluids after being purified, keeping the platelets and other essential growth factors and nutrients and possibly Stem Cells, to help regenerating and repairing the damage tissues.

While this method is widely adopted in various clinical conditions, its effectiveness in treating erectile dysfunction is yet to be determined

Whilst there are several animal studies a demonstrating the improvements of the erectile tissue following PRP treatment there are no human trials supporting the above.

Stem cell therapy:

Stem cells are “toti-potential” and their nature with the ability to grow and regenerate and eventually specialize into functional sells according to the organ they are being introduced to

There are few but reliable human studies mainly in treating men with erectile dysfunction following radical prostatectomy with the stem cell therapy and the results are very encouraging with more than 80% success in terms of improving erections and penetration until orgasm. However, the number of participants in these trials as very limited.

Stem Cells and LiESWT combined:

The aim of injecting the Stem Cells is to direct them into the targeted area with the aim of repairing and regenerating cells and resultant improvement of the function of that organ.

Stem Cells, however, need guidance to go to the affected area. There are several animal studies demonstrating and using microtrauma to the target in the organs followed by injection of Stem Cells with the resultant of higher concentration of those cells to go to the affected tissue.

Hence, logically, by combining low intensity ESWT and stem cell therapy at the same time might improve the delivery of the stem cells and the two methods would yield more encouraging results in treating erectile dysfunction.

Ongoing studies regarding the above are being carried out and the results are anxiously awaited

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Stem Cell Therapy in Male Sexual Dysfunction:

Posted on by Dr. Ali Thwaini

Erectile dysfunction is becoming a common urological problem affecting men worldwide, with almost 40% of men at and above the age of 40 years being affected by the disease, at various levels.

Whilst there are several conservative and interventional treatments for erectile dysfunction, they would treat but not cure the disease.

What is Stem cells

Stem cells exist as undifferentiated cells. They are present in the embryonic and adult stages of life and are considered as a source for differentiated cells that make up the building blocks of tissue and organs.

Due to their abundant source and high differentiation potential, stem cells are considered as potential new therapeutic agents for various medical conditions.

Recently, there has been a vested interest to investigate their use in male sexual dysfunction.

Stem Cell Therapy for Erectile Dysfunction

According to the European Association of Urology’s latest press release, new clinical trial results demonstrated the ability of stem cells to restore sufficient erectile function to allow previously impotent men to have spontaneous intercourse. This is the first time stem cell therapy has produced patients who have recovered sufficient erectile function to enable intercourse.

In recent years several groups have worked to develop stem cell therapy as a cure for erectile dysfunction. None of the male participants reported significant side effects over the trial period, or in the following year. Within 6 months of the treatment, 8 out of the 21 patients reported that they had recovered sufficient erectile function to achieve penetrative) sexual activity. This improvement has been maintained for a year, indicating that this treatment may confer long-term benefits.

Stem Cell Therapy Results

Results presented at the European Association of Urology conference in London show that 8 out of 21 have successfully regained sexual function.

We use stem cells taken from abdominal fat cells via liposuction (under local anesthetic as an office-based procedure). After isolating the stem cells, they were injected into the corpus cavernosum area of the penis. The patients are able to be discharged the same day.

Is stem cell therapy for ED Safe

This treatment is suitable for men seeking to improve their sexual performance without taking medication and/or any other external treatment, also the patient with Diabetes, Hypertension, and other diseases can benefit from this safe treatment.

Some patients might feel the benefit immediately after the treatment, but the majority will feel gradual improvement over the next 2 to 3 months, with the maximum effects achieved at 6 months.

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Stem Cell Therapy in Male Factor Infertility: Research Proposal:

Posted on by Dr. Ali Thwaini

Background:

More than 10% of couples in the world experience fertility problems. Infertility, defined as failure to conceive a clinically detectable pregnancy after >12 months of unprotected intercourse, is a common condition, reported by 1 in 6 couples.

https://www.youtube.com/watch?v=0ZryWiMWyE8&feature=youtu.be

Stem cells exist as undifferentiated cells. They are present in the embryonic and adult stages of life and are considered as a source for differentiated cells that make up the building blocks of tissue and organs.

Due to their abundant source and high differentiation potential, stem cells are considered as potential new therapeutic agents for the treatment of infertility. Stem cells could be stimulated in vitro to multiply and then are utilized in vivo to “awaken’ the dormant spermatogonia” and are theoretically a potential source to develop various numbers of specialized cells including male and female gametes suggesting their potential use in reproductive medicine. During the past few years, considerable progress in the derivation of male germ cells from pluripotent stem cells has been made. In addition, stem cell-based strategies for ovarian regeneration and oocyte production have been proposed as future clinical therapies for treating infertility in women.

There are several sources for stem cells: Embryonic-derived stem cells (ESC), extra-embryonic derived SC, and mesenchymal derived SC. Each has their advantages and disadvantages. In this contest of male factor infertility, another source of stem cells could exit, albeit, a sparse source; this is derived from autologous Spermatogonial stem cells. Whilst harvesting them is a relatively simple procedure at an outpatient setting, and there are no ethical nor moral issues with harvesting them, they are relatively small numbers in the testis; hence, extracting them would be rather difficult and it is challenging to be maintained in culture. Moreover, there is a risk of immune rejection.

Challenges with stem cell therapy in male factor infertility:

Besides genetic factors, azoospermia also occurs due to injuries, exposure to toxicants, immune-suppressive and anticancer treatments. However, a large proportion of infertile males are diagnosed as idiopathic with unknown causes, reflecting poor understanding of the mechanisms regulating spermatogenesis and sperm function in humans.
While several sources exit to cultivate and improve stem cells for particular functions, generating pluripotent stem cells that have the potential to differentiate and undergo mitosis followed by meiosis into haploid cells remains challenging.
There have been few animal studies (particularly mice) where autologous mouse induced plutipotent cells have been produced (miPSC). Those actually were cultivated into mature spermatogonia and early spermatids. However, only a few studies made successful in producing spermatozoa in mice. This is yet to extrapolate and translate into human trials.

However, there are few human trials where a successful culture of hiPSC was achieved, resulting in spermatogonia and few spermatids.

Possible sources of stem cells:

These can be derived from either embryo of the placenta (the former might have ethical problems and both might be associated with future, though minor, risks of mutations). Other cells are derived from adult bone marrow and fat cells, which are rich in stem cells.
The function of stem cells in male factor infertility can be divided into three possible functions:

  1. Stem cells are self-homing, and when injected into the human body, they can differentiate into the cells types native to these organs and parts. In this scenario, spermatogonial stem cells (SSC), travel to their niches upon transplantation into sterile testes. The transplanted SSCs then attach to the Sertoli cells and closely connect the blood-testicular barrier (BTB) to migrate to their niche on the basement membrane
  2. The second type involves the activation of dormant and suppressing cells. The growth and development of the human body is accomplished through cell division. With age, some cells stop undergoing normal cell cycles after division and show a state of functional dormancy. Stem cells can activate dormant cells and suppressor cells and encourage them to re-enter the cell cycle, proliferating by division. This has been well demonstrated with chemotherapy-induced premature ovarian failure (POF).
  3. The third type involves the paracrine secretion of various enzymes, proteins, and cytokines to promote cell proliferation, inhibit apoptosis of functional cells, and differentiate existing tissue progenitor cells into tissue cells in order to repair damaged tissues and grow new tissues. Spermato-genesis is a process regulated by testosterone, endocrine, and paracrine secretion/autocrine factors, such as the IL-1 family.
  4. The fourth type involves the exertion of an immunosuppressive function through cell-cell contact and secretion of soluble factors, inhibiting the proliferation of natural killer cells.
  5. The fifth type involves the promotion of the recovery of intercellular signaling. The signal molecule of the cell interacts with the receptor protein on the cell membrane, causing a conformational change in the receptor and the subsequent production of a new signal substance inside the cell. This triggers a response, such as an ion permeability, cell shape change, or some other cellular function change.

There are several ways of retrieving SSC, simply shown I the figure below:

Flow chart showing different pathways of potential utilization of stem cells into spermatozoa. (Left) Somatic cells may be de-differentiated into induced pluripotent stem cells (iPSCs), and then re-programmed to differentiate through germ cell lineage via transplantation into the testis seminiferous tubules, xenografting or germline stem cells in culture. (Right) SSCs may be harvested from the testis and kept as a tissue biopsy or processed into a single cell suspension. The tissue biopsy may be treated as an organ culture, autologous graft or xenograft to proliferate and differentiate SSCs to spermatozoa. Cell suspensions may be grown in culture and xenografted, autotransplanted into the testis seminiferous tubules, or differentiated in culture to harvest spermatozoa. (m) TESE, (microdissection) testicular sperm extraction.

Procedure and protocol:

The process involves two phases: 

The first phase is stem cell harvest and preparation: this involves collecting adipose-derived stem cells from accessible parts of the patients. Traditionally, adipose cells are abundant in the abdominal fat and upper thigh. This would provide the MSC that are required for mechanisms 2-5. This would be mainly helpful for men with severe oligo-asthenospermia. They are able to produce sperms albeit in sub-fertile quality and quantity.
For men who are azospermic; in addition to the above, SSC harvest is aimed from testicular biopsy (attempted at the same time) with the aim of extracting SSC for culture.

After proper patient counseling and office preparation, under aseptic technique, diluted local anesthetic with adrenaline is infiltrated into the abdominal wall on both sides. Then we allow approximately 15 minutes for the local anesthetic to work. Afterward, we harvest the abdominal fat utilizing a special fat harvest micro needle, which is well tolerated by the patients. After achieving the desired amount of the abdominal fat, it is transferred to the Stem Cell laboratory for purification and culture purposes; a process that usually takes between two to three weeks.

For azospermic men, testicular biopsy is carried out simultaneously and SSC is sent to the lab as above.

Patients are normally well enough to go home on the same day. Patients is normally counseled for the possibility of minor discomfort and bruising in the abdominal wall (and thighs, if they were utilized for the fat harvest, in thin patients).

In the second phase, the injection of stem cells into the ovaries; after two weeks from the harvest, the patient is prepared for laparoscopic injection of the stem cells into the ovaries.

This procedure is normally carried out as a Day Case under general anaesthesia. It normally takes less than an hour. After revering from the anaesthetic, the patient is normally sent home with minimal analgesics.

Proposal:

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We aim to prospectively recruit male patients with primary infertility and have a primary testicular failure (severe oligospermia or azoospermia) and include them in the above trial.

We aim to recruit a minimum number of 30 patients.

After consent, men will enter the above trial, that includes the following:

  1. Clinic consultation.
  2. Fat harvest (usually from the abdominal wall) and testicular biopsy. These are performed under local anaesthesia in a properly equipped procedure room in the outpatient department.
  3. Samples will be taken to the official Stem Cell laboratory, located in building 64 at Dubai Healthcare City for culturing.
  4. Patients will be sent the home the same day on symptomatic treatment if needed.
  5. Patients will be invited again to the clinic after two-three weeks when mesynchymal stem cells (MSC-from fat) and spermatogonia stem cells (SSC) would have been adequately cultured and are injected back into the testes under local anaesthesia and ultrasound guidance.
  6. Patients will be sent home with analgesia and prophylactic antibiotics.
  7. Patients will be invited to the clinic two weeks later for follow up.
  8. Semen analysis will be tested in three months, with a possibility of obtaining testicular biopsy afterwards (depending the results of the semen analysis). This will be carried out in the persistence of azoospermia. The aim is to look for live spermatogonia or sperms at various stages of maturation. This will be happening in liaison with the fertility clinic for the potential of freezing if applicable.
  9. Results will be published upon written consent from the participants.

References:

  1. Vladislav Volarevic, Sanja Bojic, Jasmin Nurkovic, Ana Volarevic, Biljana Ljujic, Nebojsa Arsenijevic, Majlinda Lako, Miodrag Stojkovic. Stem Cells as New Agents for the Treatment of Infertility: Current and Future Perspectives and Challenges. Biomed Res Int. 2014; 2014: 507234.
  2. Fang Fang, Zili Li, Qian Zhao, Honggang Li, Chengliang Xiong. Human-induced pluripotent stem cells and male infertility: an overview of current progress and perspectives. Hum Reprod. 2018 Feb; 33(2): 188–195.
  3. Jing Wang, Chi Liu, Masayuki Fujino, Guoqing Tong, Qinxiu Zhang, Xiao-Kang Li, Hua Yan. Stem Cells as a Resource for Treatment of Infertility-related Diseases. Curr Mol Med. 2019 Sep; 19(8): 519–546.
  4. Connor M. Forbes, Ryan Flannigan, Peter N. Schlegel. Spermatogonial stem cell transplantation and male infertility: Current status and future directions. Arab J Urol. 2018 Mar; 16(1): 171–180.

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