Japan’s Sugiyama Clinic registers a clinical study involving 200 patients with infertility scheduled for micromanipulation-assisted fertilization
Zona-bound sperm will be brought into close contact with the egg cell membrane to induce membrane fusion; the primary endpoint is the rate of euploid embryos on PGT-A
A new micromanipulation-assisted fertilization method that induces fusion between sperm and egg membranes without directly penetrating the egg cell membrane, or oolemma, with a microinjection needle is entering a full clinical comparison with conventional piezo-assisted intracytoplasmic sperm injection, hereafter PIEZO-ICSI.
Conventional intracytoplasmic sperm injection, hereafter ICSI, places sperm inside an injection needle and delivers it directly into the egg’s cytoplasm. In contrast, assisted sperm fusion insemination, hereafter ASFI, carries sperm to the egg cell membrane and brings the sperm head into close contact with it to induce fusion between the sperm and egg membranes. PIEZO-ICSI, meanwhile, is a micromanipulation-assisted fertilization technique that uses extremely fine vibrations to place a single sperm directly inside an egg.
Researchers at Japan’s Sugiyama Clinic are beginning a prospective clinical study comparing the outcomes of ASFI, which does not directly puncture the egg cell membrane with a needle, with conventional piezo-assisted ICSI.
The two methods will be applied in 200 patients with infertility who need micromanipulation-assisted fertilization. The researchers plan to follow not only fertilization and embryo development but also the proportion of embryos with a normal chromosome number and subsequent pregnancy and birth outcomes.
It omits the egg membrane puncture central to ICSI
What distinguishes ASFI—assisted sperm fusion insemination—is not simply the type of needle used. The key is that the egg cell membrane is not artificially disrupted during fertilization.
In conventional ICSI, sperm is placed inside a microinjection needle. The needle passes through the zona pellucida and penetrates the egg cell membrane before releasing the sperm into the cytoplasm.
PIEZO-ICSI also uses piezo pulses to manipulate the injection needle and reduce mechanical stress on the egg. Nevertheless, its underlying principle is the same: the egg cell membrane is ultimately penetrated, and sperm is injected into the cytoplasm.
With ASFI, by contrast, immature or degenerated eggs are first incubated with motile sperm. Sperm that have bound to the zona pellucida are then retrieved and moved into the perivitelline space—the space between the zona pellucida and the cell membrane of a mature MII egg, at metaphase II of meiosis. The sperm head is then brought into close contact with the egg cell membrane to induce adhesion and membrane fusion. The injection needle passes through the zona pellucida but does not penetrate the egg cell membrane itself.
There is also a biological reason for specifically using sperm that have bound to the zona pellucida.
Sperm attachment to the zona pellucida, the egg’s outermost layer, is an important step indicating whether the sperm has properly prepared for fertilization.
In an earlier study, 98.0% of sperm attached to the zona pellucida had undergone the acrosome reaction, a change needed to fertilize an egg. Among sperm near the egg but not attached to the zona pellucida, that proportion was only 28.6%.
The researchers selected these sperm that were ready for fertilization, placed them close to the egg cell membrane, and encouraged the sperm and egg to fuse.
The starting point was egg degeneration after ICSI
Egg degeneration following ICSI was the reason the researchers developed ASFI. Although ICSI technology has advanced and piezo-assisted methods have been introduced, the disruption of the egg cell membrane by an injection needle cannot be eliminated altogether. Eggs with particularly fragile membranes may fail to recover after injection and degenerate.
ASFI omits precisely this step. Instead of disrupting the egg cell membrane with an injection needle, it uses the biological process of membrane fusion between sperm and egg.
The researchers believe that, in theory, this approach may reduce the mechanical damage that can occur during ICSI while preserving the ability to achieve fertilization. A separate protocol standardizing the laboratory procedures for ASFI has also recently been published.
In 24 patients and 197 eggs: 88% fertilization and zero egg degeneration
This is not the first time ASFI has been used in humans.
The researchers previously compared ASFI with conventional ICSI using 197 eggs retrieved from 24 patients with infertility. Eggs from each patient were divided into two groups: one underwent ASFI and the other conventional ICSI, allowing fertilization and embryo development outcomes to be examined.
The results were intriguing. The proportion of normally fertilized eggs was 88.0% with ASFI, higher than the 70.2% with conventional ICSI. Egg degeneration—damage during the procedure that leaves an egg unable to develop further—occurred in 8.8% of eggs undergoing conventional ICSI, but there were no cases with ASFI.
The proportion of embryos available for subsequent transfer or freezing was also higher with ASFI. However, some measures of embryo development, including the rate of development to the blastocyst stage, did not show a clear difference between the two methods.
These findings alone do not establish that ASFI is better than conventional ICSI. It was a small study involving only 24 patients, and the comparator was conventional ICSI rather than the piezo-assisted ICSI being used in the new study.
Most importantly, the data were insufficient to determine not just whether eggs fertilized successfully but how many embryos with a normal chromosome number were produced and how often treatment led to pregnancy and birth. That is why the follow-up study involving 200 patients is now beginning.
The central endpoint is the euploid embryo rate, beyond fertilization alone
This study will look at more than whether fertilization was successful. The researchers’ main focus is how many embryos are produced with a normal chromosome number confirmed by PGT-A. Even a high fertilization rate offers limited benefit if it does not lead to embryos that develop normally and can actually be transferred.
After the two methods are applied, the researchers will compare the proportion of normally fertilized eggs, the number damaged during the procedure, the number that fail to fertilize, and how successfully fertilized eggs develop into blastocysts. Where PGT-A is performed, they will examine not only chromosomally normal embryos but also embryos with an abnormal chromosome number and mosaic embryos containing a mixture of normal and abnormal cells.
The study will not end there. After the resulting embryos are transferred, the researchers will track implantation, pregnancy, and miscarriage, and ultimately confirm whether a live birth occurs.
What the study seeks to establish is whether ASFI merely increases fertilization rates or whether it can become a fertilization method that produces healthy embryos and leads to pregnancy and birth.
This is not a randomized trial: ASFI and PIEZO-ICSI will alternate
There is an important point to keep in mind when interpreting the eventual results. The 200 patients will not be randomly divided into two groups, with one receiving ASFI and the other piezo-assisted ICSI. Instead, the researchers will alternate the methods, using ASFI one month and piezo-assisted ICSI the next.
Nor will every patient treated during an “ASFI month” necessarily receive ASFI. The method requires enough motile sperm that are ready to fertilize an egg, and successful attachment of sperm to the egg’s outer zona pellucida must also be confirmed. If these conditions are not met, treatment will be switched from ASFI to conventional piezo-assisted ICSI.
Put simply, this is not a trial that splits 200 patients in half for a head-to-head contest between two fertilization methods. It will also be necessary to examine which patients could actually undergo ASFI. Therefore, whether ASFI ultimately produces better or worse results, the characteristics of the patients included in each group must be considered to interpret the findings accurately.
Whether it can replace ICSI remains to be established
It is still too early to say that ASFI is better than conventional ICSI. The earlier study found more normally fertilized eggs and fewer eggs damaged during the procedure, but it was a small study of only 24 patients. The new 200-patient study is only just beginning.
ASFI is not simpler than conventional ICSI, either. Sperm ready for fertilization must be selected, moved to a position immediately in front of the egg membrane, and encouraged to adhere to and fuse with the egg. Whether this process can be applied to every patient also remains to be established. An apparently favorable fertilization rate and broad usability in clinical infertility treatment are different questions.
Even so, this study attracts attention because the question itself is new. Until now, ICSI has evolved around the question of how to place sperm accurately inside an egg while causing as little damage as possible.
ASFI takes that question one step further.
“Must sperm be placed directly inside the egg? Could we instead bring it right up to the egg membrane and allow the sperm and egg to fuse on their own?”
The earlier small study suggested that this might be possible. The next step is to establish whether that promise holds up in a study of 200 patients and whether it extends beyond successful fertilization to embryos with a normal chromosome number, pregnancy, and birth.
Whether a fertilization technique that does not insert a needle into the egg can replace current ICSI remains unknown. Nevertheless, this study is worth watching because it has begun to question the long-standing ICSI approach of placing sperm directly inside the egg.
Sources
This article draws on Sugiyama Clinic’s “Prospective comparative study of the clinical outcomes of assisted sperm fusion insemination (ASFI) and piezo-assisted intracytoplasmic sperm injection (PIEZO-ICSI),” registered in Japan’s UMIN Clinical Trials Registry on September 10, 2026 (UMIN000062866), and the earlier clinical study “Assisted sperm fusion insemination improves fertilization rates and increases usable embryos for transfer: a clinical sibling-oocyte study,” published online in F&S Reports in November 2024. The earlier study analyzed 197 eggs from 24 patients with infertility. DOI: 10.1016/j.xfre.2024.11.006.
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